Document Detail


Radionuclide imaging of angiotensin II type 1 receptor upregulation after myocardial ischemia-reperfusion injury.
MedLine Citation:
PMID:  21078800     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
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).
CONCLUSION: 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:
Takahiro Higuchi; Kenji Fukushima; Jinsong Xia; William B Mathews; Riikka Lautamäki; Paco E Bravo; Mehrbod S Javadi; Robert F Dannals; Zsolt Szabo; Frank M Bengel
Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't     Date:  2010-11-15
Journal Detail:
Title:  Journal of nuclear medicine : official publication, Society of Nuclear Medicine     Volume:  51     ISSN:  1535-5667     ISO Abbreviation:  J. Nucl. Med.     Publication Date:  2010 Dec 
Date Detail:
Created Date:  2010-11-24     Completed Date:  2010-12-22     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  0217410     Medline TA:  J Nucl Med     Country:  United States    
Other Details:
Languages:  eng     Pagination:  1956-61     Citation Subset:  IM    
Affiliation:
Division of Nuclear Medicine, Russell H Morgan Department of Radiology and Radiological Sciences, Johns Hopkins University, Baltimore, Maryland, USA.
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MeSH Terms
Descriptor/Qualifier:
Angiotensin II / diagnostic use
Angiotensin II Type 1 Receptor Blockers / pharmacology
Angiotensin-Converting Enzyme Inhibitors / pharmacology
Animals
Autoradiography
Enalapril / pharmacology
Feasibility Studies
Male
Myocardial Reperfusion Injury / metabolism*,  radionuclide imaging*
Myocardium / metabolism
Positron-Emission Tomography
Pyridines / pharmacology
Radiopharmaceuticals / diagnostic use
Rats
Rats, Wistar
Receptor, Angiotensin, Type 1 / biosynthesis*
Renin-Angiotensin System / physiology
Tetrazoles / pharmacology
Tissue Distribution
Valine / analogs & derivatives,  pharmacology
Grant Support
ID/Acronym/Agency:
1R01HL092985/HL/NHLBI NIH HHS; 5R01DK050183/DK/NIDDK NIH HHS; 5U24CA092871-10/CA/NCI NIH HHS
Chemical
Reg. No./Substance:
0/Angiotensin II Type 1 Receptor Blockers; 0/Angiotensin-Converting Enzyme Inhibitors; 0/KR 31080; 0/Pyridines; 0/Radiopharmaceuticals; 0/Receptor, Angiotensin, Type 1; 0/Tetrazoles; 11128-99-7/Angiotensin II; 137862-53-4/valsartan; 7004-03-7/Valine; 75847-73-3/Enalapril

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine


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