Suppression of Choroidal Neovascularization by Inhibiting Angiotensin-Converting Enzyme: Minimal Role of Bradykinin

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