Purpose. To evaluate blood flow reduction and topographic optic nerve changes after the local administration of endothelin-1 in vivo, delivered to the perineural region of the anterior optic nerve in the rabbit. Methods. Endothelin-1 (five rabbits) in a dosage of 0.1 mu g/day or balanced salt solution (two rabbits) was delivered to the perineural region of the anterior optic nerve with osmotically driven minipumps. Optic nerve blood Row was determined by the colored microspheres technique after 14 days of local endothelin-l or balanced salt solution administration to the microvasculature of tile optic nerve. In addition, optic nerve blood flow was determined in two rabbits that had no minipump implants. The morphologic changes induced by reduction of blood Row were assessed in five additional rabbits implanted with osmotically driven minipumps containing endothelin (0.1 mu g/day). These rabbits were observed for 8 weeks, and the morphologic optic nerve changes were monitored with a confocal scanning laser ophthalmoscope, Results, Independent of intraocular pressure, endothelin-l induced a decrease in blood flow of approximately 38% in the experimental eye, compared to the decrease induced by balanced salt solution or to the decrease in rabbits without minipumps (analysis of covariance, P = 0.0092). Multivariate statistical analysis showed a significant change in topometric parameters (cup area, cup depth, rim volume) obtained with a confocal scanning laser ophthalmoscope, indicating an increase in optic nerve cupping and a decrease of tile perineural rim volume in the experimental eyes (P = 0.017). Conclusions. The current results suggest that morphologic optic nerve alterations can be induced experimentally in the rabbit model after ischemia produced by the local administration of endothelin-l to the perineural region of the anterior optic nerve.