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L. Guo, F.W. Fitzke, V. Luong, F.C. Schlichtenbrede, M.F. Cordeiro; Effect of Degree of Intraocular Pressure (IOP) Elevation on Glaucomatous Damage in a Rat Model of Chronic Ocular Hypertension (OHT) . Invest. Ophthalmol. Vis. Sci. 2003;44(13):3338.
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Purpose: To investigate the significance of the degree and duration of IOP elevation on structural and functional parameters using in vivo and histological assessments of optic nerve head (ONH) damage and retinal function in OHT rats. Methods: 20 DA rats underwent hypertonic saline injections into the episcleral venous system to induce glaucoma in the left eye according to the method described by Morrison et al. To investigate the effect of the level of IOP elevation, animals were randomly assigned to a further injection at 2 months ("double surgery" n=11, "single surgery" n=9). Contralateral, unoperated eyes acted as controls. Measurement of intraocular pressures (IOP), imaging with scanning laser ophthalmoscopy (SLO) and optical coherence tomography (OCT), and electroretinography (ERG) were performed under general anaesthetic at set time points. Animals were killed after 4 months following which enucleated whole eyes were analysed immunohistologically for retinal ganglion cells (RGC), apoptosis and ONH damage. Results: The integral IOP (ΔIOP integral), defined as the integral of IOP elevation over time (or area-under-the curve), was significantly higher in the "double surgery" group (p<0.001; mean: "single surgery" 445.8 ±93.1, "double surgery" 784.8±92.3 mmHg days). The occurrence of optic disc cupping was found to be significantly related to time (p<0.001) in both groups. However, the degree of optic cupping, was found to be positively correlated with ΔIOP integral (p<0.01, Spearman r=0.767), with "double surgery" being associated with increased cupping. Functionally, increased ΔIOP integral was associated with a greater decrease in the ERG b-wave amplitude. ONH damage was confirmed histologically and correlated strongly with in vivo assessment. Finally, RGC counts were lower with a significant increase in RGC apoptosis (p<0.05) detected in eyes with a high ΔIOP integral (>500 mmHg days). Conclusions: As expected, double surgery produced eyes with a higher degree of IOP elevation over the study period. Progressive cupping, optic nerve head damage and retinal function were all found to correlate with the ΔIOP integral in this rat model of glaucoma. This study demonstrates that the combined factors of the level and the duration of IOP elevation determine structural and functional changes associated with glaucoma. This may explain why even low degrees of elevated IOP can lead to progressive glaucomatous damage with time.
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