Radionuclide imaging of angiotensin II type 1 receptor upregulation after myocardial ischemia-reperfusion injury

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

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Abstract

The renin-angiotensin system (RAS) mediates proapoptotic, pro-fibrotic, 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 11C-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 (11C-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 11C-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 11C-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.

Original languageEnglish
Pages (from-to)1956-1961
Number of pages6
JournalJournal of Nuclear Medicine
Volume51
Issue number12
DOIs
Publication statusPublished - Dec 1 2010
Externally publishedYes

Keywords

  • Angiotensin
  • Molecular imaging
  • Myocardial infarction
  • PET
  • Receptor

ASJC Scopus subject areas

  • Radiology Nuclear Medicine and imaging

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    Higuchi, T., Fukushima, K., Xia, J., Mathews, W. B., Lautamäki, R., Bravo, P. E., Javadi, M. S., Dannals, R. F., Szabo, Z., & Bengel, F. M. (2010). Radionuclide imaging of angiotensin II type 1 receptor upregulation after myocardial ischemia-reperfusion injury. Journal of Nuclear Medicine, 51(12), 1956-1961. https://doi.org/10.2967/jnumed.110.079855