Model of endothelin-1-induced chronic optic neuropathy in rat.

PURPOSE To describe a model of chronic endothelin (ET)-1 administration to the optic nerve and evaluate its effect on retinal ganglion cell (RGC) and axon survival in rat. METHODS Osmotic minipumps were surgically implanted in one eye of 113 Brown Norway rats to deliver 0.05, 0.10, 0.20, or 0.40 microg ET-1 per day (3.3, 6.7, 13.4, and 26.8 microM, respectively), or balanced salt solution (BSS) to the immediate retrobulbar optic nerve; the fellow untreated eye served as the control. Before pump implantation, RGCs were retrogradely labeled with fluorochrome. Animals were killed at 21, 42, or 84 days. RGC survival was expressed as the ratio of RGC counts in experimental versus control eyes in wholemounted retinas, whereas axon survival was expressed similarly from electron micrographs of the optic nerves. Serial optic disc changes were evaluated using scanning laser tomography. The effect of ET-1 (3 microL topical application of 10(-5) M) on blood flow in the surgically exposed optic nerve was measured using laser Doppler flowmetry in a separate group of five animals. RESULTS ET-1 led to a mean reduction in optic nerve blood flow of 68%. There were no significant differences in RGC survival among the four ET-1 doses used in this study. Pooled across all ET-1 doses, RGC survival decreased incrementally at 21, 42, and 84 days (P < 0.001; mean +/- SD, 0.77 +/- 0.25, 0.60 +/- 0.27, and 0.50 +/- 0.26, respectively) and was statistically significantly lower at each time point than in the BSS-treated animals. The axon survival data also showed a similar time-dependent loss. Only one of 21 animals showed significantly increased disc cupping, and there was no relationship between RGC survival and change in cupping. CONCLUSIONS. Chronic administration of ET-1 to the rat optic nerve results in a time-dependent loss of RGCs and their axons without apparent change in optic disc topography.

[1]  D. R. Anderson,et al.  Glaucoma: the damage caused by pressure. XLVI Edward Jackson memorial lecture. , 1989, American journal of ophthalmology.

[2]  M. Vidal-Sanz,et al.  Retinal ganglion cell death after different transient periods of pressure-induced ischemia and survival intervals. A quantitative in vivo study. , 1996, Investigative ophthalmology & visual science.

[3]  K. Yaoeda,et al.  Experimental glaucoma model in the rat induced by laser trabecular photocoagulation after an intracameral injection of India ink. , 1998, Japanese journal of ophthalmology.

[4]  E. Stefánsson,et al.  The impact of ocular blood flow in glaucoma , 2002, Progress in Retinal and Eye Research.

[5]  P. Kaufman,et al.  Increased elastin expression in astrocytes of the lamina cribrosa in response to elevated intraocular pressure. , 2001, Investigative ophthalmology & visual science.

[6]  A. Alm,et al.  Ocular and optic nerve blood flow at normal and increased intraocular pressures in monkeys (Macaca irus): a study with radioactively labelled microspheres including flow determinations in brain and some other tissues. , 1973, Experimental eye research.

[7]  G A Cioffi,et al.  Measurement of optic nerve blood flow with nonradioactive colored microspheres in rabbits. , 1996, Microvascular research.

[8]  M. Marmor,et al.  Dextromethorphan protects retina against ischemic injury in vivo. , 1989, Archives of ophthalmology.

[9]  W. Goto,et al.  Evaluation of Nitric Oxide Synthesis in the Optic Nerve Head in vivo Using Microdialysis and High-Performance Liquid Chromatography and Its Interaction with Endothelin-1 , 2003, Ophthalmic Research.

[10]  L. Schmetterer,et al.  Effect of endothelin and BQ123 on ocular blood flow parameters in healthy subjects. , 2001, Investigative ophthalmology & visual science.

[11]  M. Nicolela,et al.  Effects of cold-induced vasospasm in glaucoma: the role of endothelin-1. , 2003, Investigative ophthalmology & visual science.

[12]  S. Hayreh Pathogenesis of cupping of the optic disc. , 1974, The British journal of ophthalmology.

[13]  T. Yorio,et al.  Human optic nerve head astrocytes as a target for endothelin-1. , 2002, Investigative ophthalmology & visual science.

[14]  R. Sergott,et al.  The prevalence of cupping in end-stage arteritic and nonarteritic anterior ischemic optic neuropathy. , 2001, Ophthalmology.

[15]  D. R. Bacon,et al.  An in vivo model of chronic optic nerve ischemia: the dose-dependent effects of endothelin-1 on the optic nerve microvasculature. , 1995, Current eye research.

[16]  G. Dunkelberger,et al.  Optic nerve head extracellular matrix in primary optic atrophy and experimental glaucoma. , 1990, Archives of ophthalmology.

[17]  L. Wheeler,et al.  Neuroprotection of retinal ganglion cells by brimonidine in rats with laser-induced chronic ocular hypertension. , 2001, Investigative ophthalmology & visual science.

[18]  R S Harwerth,et al.  Ganglion cell losses underlying visual field defects from experimental glaucoma. , 1999, Investigative ophthalmology & visual science.

[19]  A. P. Shepherd,et al.  Laser-Doppler Blood Flowmetry , 2010, Developments in Cardiovascular Medicine.

[20]  J. Morrison,et al.  The effect of chronically elevated intraocular pressure on the rat optic nerve head extracellular matrix. , 1996, Experimental eye research.

[21]  J. Williamson,et al.  Increased sciatic nerve blood flow in diabetic rats: assessment by "molecular" vs. particulate microspheres. , 1997, The American journal of physiology.

[22]  Dao-Yi Yu,et al.  Isolated preparations of ocular vasculature and their applications in ophthalmic research , 2003, Progress in Retinal and Eye Research.

[23]  P. Kaufman,et al.  Differential expression of matrix metalloproteinases in monkey eyes with experimental glaucoma or optic nerve transection , 2003, Brain Research.

[24]  A. Sommer,et al.  Intraocular pressure and glaucoma. , 1989, American journal of ophthalmology.

[25]  H. Quigley,et al.  Laser energy levels for trabecular meshwork damage in the primate eye. , 1983, Investigative ophthalmology & visual science.

[26]  A. E. Maumenee,et al.  Optic atrophy and glaucomatous cupping. , 1978, American journal of ophthalmology.

[27]  H. Quigley,et al.  Cupping of the optic disc in ischemic optic neuropathy. , 1977, Transactions. Section on Ophthalmology. American Academy of Ophthalmology and Otolaryngology.

[28]  R. Massof,et al.  Morphologic changes in the lamina cribrosa correlated with neural loss in open-angle glaucoma. , 1983, American journal of ophthalmology.

[29]  B. Chauhan,et al.  Effect of intraocular pressure on optic disc topography, electroretinography, and axonal loss in a chronic pressure-induced rat model of optic nerve damage. , 2002, Investigative ophthalmology & visual science.

[30]  S. Cranstoun,et al.  Effects of endothelin-1 on optic nerve head blood flow in cats. , 1996, Journal of ocular pharmacology and therapeutics : the official journal of the Association for Ocular Pharmacology and Therapeutics.

[31]  G. Cull,et al.  Depth of penetration of scanning laser Doppler flowmetry in the primate optic nerve. , 2001, Archives of ophthalmology.

[32]  G Michelson,et al.  Two dimensional mapping of the perfusion of the retina and optic nerve head. , 1995, The British journal of ophthalmology.

[33]  J. Pederson,et al.  Laser-induced primate glaucoma. II. Histopathology. , 1984, Archives of ophthalmology.

[34]  J. Jonas,et al.  Optic disc morphology in eyes after nonarteritic anterior ischemic optic neuropathy. , 1993, Investigative ophthalmology & visual science.

[35]  S. Sharma,et al.  Chronic ocular hypertension following episcleral venous occlusion in rats. , 1995, Experimental eye research.

[36]  D. Wilson,et al.  An endothelin-1 induced model of optic nerve ischemia in the rabbit. , 1996, Investigative ophthalmology & visual science.

[37]  G. Cioffi,et al.  The Effect of Chronic Ischemia on the Primate Optic Nerve , 1999, European journal of ophthalmology.

[38]  C. K. Adams,et al.  Slow axonal protein transport and visual function following retinal and optic nerve ischemia. , 1975, Investigative ophthalmology.

[39]  T. Yorio,et al.  Endothelin: is it a contributor to glaucoma pathophysiology? , 2002, Journal of glaucoma.

[40]  C. Meshul,et al.  A rat model of chronic pressure-induced optic nerve damage. , 1997, Experimental eye research.

[41]  T. Lüscher,et al.  Effects of calcium channel blockers on the response to endothelin-1, bradykinin and sodium nitroprusside in porcine ciliary arteries. , 1995, Experimental eye research.

[42]  A. Bill,et al.  Ocular effects of endothelin-1 in the cat. , 1992, Current eye research.

[43]  D. R. Bacon,et al.  An Endothelin‐1‐Induced Model of Chronic Optic Nerve Ischemia in Rhesus Monkeys , 1996, Journal of glaucoma.

[44]  M. Nicolela,et al.  Color Doppler imaging in patients with asymmetric glaucoma and unilateral visual field loss. , 1996, American journal of ophthalmology.

[45]  T. Yorio,et al.  Effects of endothelin-1 on components of anterograde axonal transport in optic nerve. , 2002, Investigative ophthalmology & visual science.

[46]  D. Tsang,et al.  Acute responses of rat retina after optic nerve ligation: a biochemical and histochemical study , 1985, Brain Research.

[47]  R. T. Hart,et al.  Deformation of the lamina cribrosa and anterior scleral canal wall in early experimental glaucoma. , 2003, Investigative ophthalmology & visual science.

[48]  W. Andrzejewska,et al.  Changes in the extracellular matrix of the human optic nerve head in primary open-angle glaucoma. , 1990, American journal of ophthalmology.

[49]  H. Quigley,et al.  Translimbal laser photocoagulation to the trabecular meshwork as a model of glaucoma in rats. , 2002, Investigative ophthalmology & visual science.

[50]  D. Gaasterland,et al.  Experimental glaucoma in the rhesus monkey. , 1974, Investigative ophthalmology.

[51]  S. Hayreh Inter-individual variation in blood supply of the optic nerve head , 1985, Documenta Ophthalmologica.

[52]  H. Quigley,et al.  Quantitative study of collagen and elastin of the optic nerve head and sclera in human and experimental monkey glaucoma. , 1991, Current eye research.

[53]  Sadao Kimura,et al.  A novel potent vasoconstrictor peptide produced by vascular endothelial cells , 1988, Nature.

[54]  J. Kiel,et al.  Endothelin modulation of choroidal blood flow in the rabbit. , 2000, Experimental eye research.