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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.
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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.
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.
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 Ã‘Âµm3 for 1 mg/kg, 415,041 + 137,207 Ã‘Âµm3 for 10 mg/kg and 409,669 + 87,086 Ã‘Âµm3 for 40 mg/kg), compared with vehicle-treated mice (550,345 + 108,015 Ã‘Âµm3). 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.
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.
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