title: Radionuclide imaging of angiotensin II type 1 receptor upregulation after myocardial ischemia-reperfusion injury.
abstract: The renin-angiotensin system (RAS) mediates proapoptotic, profibrotic, and proinflammatory processes in maladaptive conditions. Activation after myocardial infarction may initialize and promote cardiac remodeling. Using a novel positron-emitting ligand, we sought to determine the presence and time course of regional myocardial upregulation of the angiotensin II type 1 receptor (AT1R) and the blocking efficacy of various anti-RAS agents.
  
  
  METHODS
  In male Wistar rats (n = 31), ischemia-reperfusion damage was induced by 20- to 25-min ligation of the left coronary artery. The AT1R blocker (11)C-2-butyl-5-methoxymethyl-6-(1-oxopyridin-2-yl)-3-[[2-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl]-3H-imidazo[4,5-b]pyridine ((11)C-KR31173) was injected intravenously at different times until 6 mo after surgery and sacrifice. Autoradiography, histology, and immunohistochemistry were performed for ex vivo validation. Additional in vivo PET was conducted in 3 animals. A second series of experiments (n = 16) compared untreated animals with animals treated with oral valsartan (50 mg/kg/d), oral enalapril (10 mg/kg/d), and complete intravenous blockage (SK-1080, 2 mg/kg, 10 min before imaging).
  
  
  RESULTS
  Transient regional AT1R upregulation was detected in the infarct area, with a peak at 1-3 wk after surgery (autoradiographic infarct-to-remote ratio, 1.07 ± 0.09, 1.68 ± 0.34, 2.54 ± 0.40, 2.98 ± 0.70, 3.16 ± 0.57, 1.86 ± 0.65, and 1.28 ± 0.27 at control, day 1, day 3, week 1, week 3, month 3, and month 6, respectively). The elevated uptake of (11)C-KR31173 in the infarct area was detectable by small-animal PET in vivo, and it was blocked completely by intravenous SK-1080. Although oral treatment with enalapril did not reduce focal tracer uptake, oral valsartan resulted in partial blockade (infarct-to-remote ratio, 2.94 ± 0.52, 2.88 ± 0.60, 2.07 ± 0.25, and 1.26 ± 0.10 for no treatment, enalapril, valsartan, and SK-1080, respectively).
  
  
  CONCLUSIONS
  After ischemic myocardial damage in a rat model, transient regional AT1R upregulation is detectable in the infarct area using (11)C-KR31173. Inhibitory effects of the clinical AT1R blocker valsartan can be identified, whereas blockage of upstream angiotensin-converting enzyme with enalapril does not affect AT1R density. These results provide a rationale for subsequent testing of AT1R-targeted imaging to predict the risk for ventricular remodeling and to monitor the efficacy of anti-RAS drug therapy.
authors.affiliation: Division of Nuclear Medicine, Russell H Morgan Department of Radiology and Radiological Sciences, Johns Hopkins University, Baltimore, Maryland, USA.
authors.forename: Takahiro
authors.initials: T
authors.lastname: Higuchi
authors.forename: Kenji
authors.initials: K
authors.lastname: Fukushima
authors.forename: Jinsong
authors.initials: J
authors.lastname: Xia
authors.forename: William B
authors.initials: WB
authors.lastname: Mathews
authors.forename: Riikka
authors.initials: R
authors.lastname: Lautamäki
authors.forename: Paco E
authors.initials: PE
authors.lastname: Bravo
authors.forename: Mehrbod S
authors.initials: MS
authors.lastname: Javadi
authors.forename: Robert F
authors.initials: RF
authors.lastname: Dannals
authors.forename: Zsolt
authors.initials: Z
authors.lastname: Szabo
authors.forename: Frank M
authors.initials: FM
authors.lastname: Bengel
mesh_terms: D000804:Angiotensin II; D047228:Angiotensin II Type 1 Receptor Blockers / Q000494:pharmacology; D000806:Angiotensin-Converting Enzyme Inhibitors / Q000494:pharmacology; D000818:Animals; D001345:Autoradiography; D004656:Enalapril / Q000494:pharmacology; D005240:Feasibility Studies; D008297:Male; D015428:Myocardial Reperfusion Injury / Q000000981:diagnostic imaging* / Q000378:metabolism*; D009206:Myocardium / Q000378:metabolism; D049268:Positron-Emission Tomography; D011725:Pyridines / Q000494:pharmacology; D019275:Radiopharmaceuticals; D051381:Rats; D017208:Rats, Wistar; D044140:Receptor, Angiotensin, Type 1 / Q000096:biosynthesis*; D012084:Renin-Angiotensin System / Q000502:physiology; D013777:Tetrazoles / Q000494:pharmacology; D014018:Tissue Distribution; D014633:Valine / Q000031:analogs & derivatives / Q000494:pharmacology; D000068756:Valsartan
chemical_list: D047228:Angiotensin II Type 1 Receptor Blockers; D000806:Angiotensin-Converting Enzyme Inhibitors; C111727:KR 31080; D011725:Pyridines; D019275:Radiopharmaceuticals; D044140:Receptor, Angiotensin, Type 1; D013777:Tetrazoles; D000804:Angiotensin II; D004656:Enalapril; D000068756:Valsartan; D014633:Valine