Two retrograde signals influence the chick embryo's isthmo-optic nucleus, which projects to the retina: a slow-acting survival signal due to uptake of neurotrophic factors, and a fast-acting death signal initiated by calcium entry into isthmo-optic terminals due to electrical activity. The latter signal also affects dendritic reorganization. Since nitric oxide synthase is present in isthmo-optic terminals and their retinal target cells, we have tested its possible role in the fast-acting signal. Intraocular injection of nitric oxide antagonists led within 6-12 h to a reduction in the number of dying isthmo-optic neurons and slowed dendritic reorganization. Surprisingly, nitric oxide agonists had a similar fast effect on neuronal death. Although the mechanism appears to be complex, nitric oxide is involved in mediating the fast-acting retrograde signal.