May 2007
Volume 48, Issue 13
Free
ARVO Annual Meeting Abstract  |   May 2007
Suppression of Choroidal Neovascularization by Inhibiting Angiotensin-Converting Enzyme: Minimal Role of Bradykinin
Author Affiliations & Notes
  • N. Nagai
    Keio Univ School of Medicine, Tokyo, Japan
    Laboratory of Retinal Cell Biology,
    Ophthalmology,
  • Y. Oike
    Keio Univ School of Medicine, Tokyo, Japan
    Laboratory of Vascular Biology and Metabolism,
  • K. Izumi-Nagai
    Keio Univ School of Medicine, Tokyo, Japan
    Laboratory of Retinal Cell Biology,
    Ophthalmology,
  • T. Koto
    Keio Univ School of Medicine, Tokyo, Japan
    Laboratory of Retinal Cell Biology,
    Ophthalmology,
  • S. Satofuka
    Keio Univ School of Medicine, Tokyo, Japan
    Laboratory of Retinal Cell Biology,
    Ophthalmology,
  • H. Shinoda
    Keio Univ School of Medicine, Tokyo, Japan
    Laboratory of Retinal Cell Biology,
    Ophthalmology,
  • Y. Ozawa
    Keio Univ School of Medicine, Tokyo, Japan
    Laboratory of Retinal Cell Biology,
    Ophthalmology,
  • M. Inoue
    Keio Univ School of Medicine, Tokyo, Japan
    Ophthalmology,
  • K. Tsubota
    Keio Univ School of Medicine, Tokyo, Japan
    Ophthalmology,
  • S. Ishida
    Keio Univ School of Medicine, Tokyo, Japan
    Laboratory of Retinal Cell Biology,
    Ophthalmology,
  • Footnotes
    Commercial Relationships N. Nagai, Tanabe Seiyaku Co., Ltd., F; Y. Oike, None; K. Izumi-Nagai, None; T. Koto, None; S. Satofuka, None; H. Shinoda, None; Y. Ozawa, None; M. Inoue, None; K. Tsubota, None; S. Ishida, Tanabe Seiyaku Co., Ltd., F.
  • Footnotes
    Support None.
Investigative Ophthalmology & Visual Science May 2007, Vol.48, 1467. doi:https://doi.org/
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      N. Nagai, Y. Oike, K. Izumi-Nagai, T. Koto, S. Satofuka, H. Shinoda, Y. Ozawa, M. Inoue, K. Tsubota, S. Ishida; Suppression of Choroidal Neovascularization by Inhibiting Angiotensin-Converting Enzyme: Minimal Role of Bradykinin. Invest. Ophthalmol. Vis. Sci. 2007;48(13):1467. doi: https://doi.org/.

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      © ARVO (1962-2015); The Authors (2016-present)

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Abstract

Purpose:: Angiotensin-converting enzyme (ACE), also known as kininase II, functions not only to convert angiotensin I to angiotensin II, but also to cleave bradykinin to inactive fragments. Thus, ACE inhibition causes the tissue accumulation of bradykinin, exerting either of two opposite effects, anti- or pro-angiogenic action. The purpose of the current study is to investigate the role of bradykinin in the development of CNV with or without ACE inhibition.

Methods:: Laser photocoagulation was used to induce CNV in wild-type C57BL/6J mice and angiotensin II type 1 receptor (AT1-R)-deficient mice. Wild-type mice were pretreated with an ACE inhibitor imidapril (0.1, 1, 10 or 40 mg/kg body weight) with or without a bradykinin B2 receptor (B2-R) antagonist icatibant (0.1 or 0.5 mg/kg body weight) daily for 6 days before photocoagulation and the treatment were continued daily till the end of the study. CNV response was analyzed by volumetric measurements using confocal microscopy 1 week after laser injury. The mRNA and protein levels of VEGF and ICAM-1 in the retinal pigment epithelium-choroid complex were examined by RT-PCR and ELISA, respectively.

Results:: ACE inhibition led to significant suppression of CNV development to the level seen in AT1-R deficient mice. Imidapril-treated mice at the dose of 1, 10 or 40 mg/kg showed a significant (P < 0.001) decrease in the CNV volume (421,630 + 101,857 ѵm3 for 1 mg/kg, 415,041 + 137,207 ѵm3 for 10 mg/kg and 409,669 + 87,086 ѵm3 for 40 mg/kg), compared with vehicle-treated mice (550,345 + 108,015 ѵm3). Importantly, B2-R blockade together with high-dose (10 or 40 mg/kg), but not low-dose (1 mg/kg), ACE inhibition resulted in more potent suppression of CNV than ACE inhibition alone. Interestingly, B2-R blockade alone exhibited little or no effect on CNV. VEGF and ICAM-1 levels, elevated by CNV induction, were significantly (P < 0.05) suppressed by ACE inhibition. VEGF, but not ICAM-1, levels were further attenuated by B2-R blockade with ACE inhibition.

Conclusions:: These results suggest a limited contribution of the kallikrein-kinin system to the pathogenesis of CNV, in which the renin-angiotensin system plays more essential roles for facilitating angiogenesis. The present study indicates the possibility of ACE inhibition as a novel therapeutic strategy to inhibit CNV.

Keywords: choroid: neovascularization • age-related macular degeneration • drug toxicity/drug effects 
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