Positron-Emission Tomography Imaging of the Angiotensin II Subtype 1 Receptor in Swine Renal Artery Stenosis

Abstract

Abstract-The angiotensin II subtype 1 receptor (AT 1 R) has been linked to the development and progression of renovascular hypertension. In this study we applied a pig model of renovascular hypertension to investigate the AT 1 R in vivo with positron-emission tomography (PET) and in vitro with quantitative autoradiography. AT 1 R PET measurements were performed with the radioligand [ 11 C]KR31173 in 11 control pigs and in 13 pigs with hemodynamically significant renal artery stenosis; 4 were treated with lisinopril for 2 weeks before PET imaging. The radioligand impulse response function was calculated by deconvolution analysis of the renal time-activity curves. Key Words: positron-emission tomography Ⅲ angiotensin AT 1 receptor Ⅲ swine Ⅲ animal models Ⅲ renovascular hypertension R enovascular hypertension is the most common type of secondary hypertension that occurs in 2 to 4 million people in the United States. The renin-angiotensin system and its component, the angiotensin II subtype 1 receptor (AT 1 R), have been tightly linked to the development and progression of renovascular hypertension (RVH), but experimental mechanistic evidence for regulation of the AT 1 R has not been established in vivo. Antagonists against the angiotensin-converting enzyme (ACE; ACE inhibitors) or the AT 1 R (angiotensin receptor blockers) continue to play a key role in the therapy of renal hypertension and other kidney diseases. 1 Both drugs represent a "doubleedged sword," because they may deactivate regulatory effects of the renin-angiotensin system and the AT 1 R and trigger irreversible renal damage. 2 The complexity of the management of RVH raises a pressing need for an in vivo imaging technique that cannot only demonstrate reduced blood flow to the organ but also detect and monitor renal ischemia at the molecular level. [3][4][5][6] Magnetic resonance (MR) angiography (MRA) and computed tomography angiography are oriented toward depicting anatomy rather than tissue injury. 7,8 Radionuclide captopril renography has not been widely accepted 9 because of its limited accuracy in the presence of bilateral disease 10 or therapy with ACE inhibitors. 11 Inhibiting the activity of the AT 1 R with angiotensin receptor blockers or ACE inhibitors, on the other hand, is widely adapted by clinicians to protect the kidney from renal injury. [12][13][14][15][16] Probing molecular changes is expected to assist diagnosis and support prediction and evaluation of treatment success. We have identified the AT 1 R as a significant molecular imaging target because of its intricate involvement in the many aspects of renal physiology and pathology, [17][18][19] particularly in acute, subacute, and chronic complications of renal ischemia. 20,21 The AT 1 R is a key injury response protein because its continuing activation leads to stimulation of the extracellular matrix, 22 collagen deposition, glomerular remodeling, 23 inflammation, 24 apoptosis, 25 generation of oxygen species, and cell cycle arrest. 26 To this end, our group has synthesized several ...

Intrarenal Perfusion and Angiotensin II Levels Regulate In Vivo Angiotensin II Type 1 Receptor Imaging in the Kidney

“…1 These images were consistent with Ͼ70% reductions in intrarenal perfusion in the kidneys with renal artery stenosis compared with contralateral kidneys.…”

“…1 In this study, AT 1 11 C]KR31173 levels were clearly observed at 2 minutes, which were followed by marked increases in [ 11 C]KR31173 accumulation in the kidneys with stenosis at 30 minutes after injection of the radioligand. By contrast, most injected […”

“…1 It would be interesting to determine whether plasma renin activities (or concentrations) and circulating and intrarenal Ang II levels in these pigs were altered by long-term lisinopril treatment. These investigators have indeed nicely showed that intrarenal AT 1 receptor binding was inversely related to Ang II in dogs treated with high-or low-salt diet.…”

Pharmacological Characterization of KR-31125, a Novel Nonpeptide AT1 Receptor Antagonist

“…Renovascular hypertension is the most common type of secondary hypertension that occurs in 2 to 4 million people in the United States [22]. Especially, the renin angiotensin system plays a major role in the regulation of blood pressure and in the pathogenesis of hypertension [9,15].…”

Characterization of angiotensin II antagonism displayed by KR-31081, a novel nonpeptide AT1 receptor antagonist

“…Currently losartan is on the market as the first AII receptor antagonist that was launched as a novel antihypertensive agent since proven to be orally active in animals [9][10][11] and humans [12][13][14]. Recently, the application of AII receptor antagonists has expanded to ongoing trials for noninvasive diagnostics as in positron emission tomography imaging [15][16][17] …”