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N. L. Barnett, D. J. Holcombe, N. Lengefeld, G. A. Gole; Rat Retinal Glutamate Transport Is Related to Intraocular Pressure and Cellular Hypoxia. Invest. Ophthalmol. Vis. Sci. 2007;48(13):4196.
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To investigate the relationship between retinal glutamate transport activity, retinal hypoxia and IOP during acute IOP elevations of varying magnitude in the rat.
Female Dark Agouti rats were anaesthetized by ketamine/xylazine/acepromazine (10/5/0.5 mg/kg i.p.). The anterior chamber was then cannulated with a 30G needle attached to a reservoir containing 0.9% NaCl. Target IOP (20-120 mmHg, 10 mmHg increments, n=4 for each IOP) was obtained by adjusting the reservoir height. After ten minutes of IOP stabilization, 2 ul of the non-endogenous glutamate transporter substrate, D-aspartate (750 uM), was injected with a Hamilton syringe into the vitreous (final concentration 50 uM), and elevated IOP maintained for a further sixty minutes (total elevation of IOP was 70 minutes). The rats were killed immediately and the retinas fixed in 2.5% glutaraldehyde for 30 minutes. Glutamate transporter function was assessed by immunohistochemical localization of D-aspartate and retinal sections cut for histological analysis. The experiment was repeated substituting the cellular hypoxia marker, Hyproxyprobe-1, for D-aspartate.
Under control conditions, D-aspartate was preferentially taken up into the glial Müller cells by GLAST (GLutamate/ASpartate Transporter). GLAST function was maintained at pressures below 70 mmHg, whereafter an observable perturbation of function was evidenced by a decreased accumulation of D-aspartate by the Müller cells. This failure of GLAST activity correlated with the appearance of positive Hypoxyprobe-labelled cells and histological damage to the retina.
Elevated IOP above 70 mmHg reduces retinal oxygen status and alters retinal glutamate transporter function. The association between IOP, hypoxia, glutamate transporter dysfunction and retinal cell death may have important implications for the pathogenesis of IOP/ischaemic related neuropathy and neuroprotective strategies.
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