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Robin Roberts, David Bissig, Bruce A. Berkowitz; Calcium Channel Antagonism Reduces Retinal Neovascularization (NV) in Experimental ROP. Invest. Ophthalmol. Vis. Sci. 2011;52(14):3997.
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To test the hypothesis that calcium channels participate in the development of retinal NV in the rat 50/10 model.
Long-Evans (LE) rats were exposed to a 50/10 variable oxygen protocol for the first 2 weeks after birth (i.e., P0 -14) and then room air for 6 days until P20. In treatment arm A, the calcium channel antagonist diltiazem (DIL, 30 mg/kg, s.c.) was administered during P14 - 20. In arm B, rats were treated with the combination of diltiazem (30 mg/kg, s.c., during P7- 20) and nifedipine (dam, chow admix, 30 mg/kg/day, during P0-20) (DIL+NIF) or saline (s.c, during P7-20, control) and normal chow (P0 - P20). Manganese-enhanced MRI (MEMRI) was used to assess calcium channel activity. NV incidence and severity (clockhours) were also evaluated. In addition, control P50 LE rats, with and without specific L-type (NIF, 30 mg/kg, ip) and ligand-type calcium channel antagonists (4 mg/kg MK-801 ip [NMDA], and 10 mg/kg ip NBQX [AMPA]) were studied with MEMRI.
In arm A, DIL corrected (P < 0.05) the supernormal intraretinal manganese uptake at P20 but did not (P > 0.05) reduce NV severity, relative to the non-treated group. In arm B, DIL+NIF reduced NV severity by 23% (P < 0.05) compared to that of the saline treated and non-treated control groups. In all cases, NV incidence was 100%. In control rats, NIF, and not NMDA or AMPA antagonism, reduced intra-retinal manganese uptake, indicating that the L-type voltage-gated calcium channels are a major manganese entry route into the retina.
Abnormal L-type calcium channel opening induced during the 50/10 procedure appears to be a pathogenic factor in the development of retinal NV in an experimental ROP model.
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