Somatostatin and its receptors (ssts) are found in the retina. Recent evidence suggested the involvement of sst 2 A and sst 2 B receptors in the regulation of nitric oxide (NO) (). In this study, we investigated further the localization of sst 1 , sst 3 -sst 5 , and the possible involvement of all subtypes, present in the rat retina, in the regulation of NO production. Polyclonal antibodies raised against sst 1 , sst 3 - 5 were applied to 10-14 μm cryostat sections of rat retinas fixed in paraformaldehyde. NADPH-diaphorase reactivity was assessed histochemically. The levels of NO in rat retinal explants were assessed by the production of its stable metabolites NO 2 - and NO 3 - . sst 1 immunofluorescence was detected mainly in the retinal pigment epithelium, blood vessels of the inner retina, where it was colocalized with NADPH-diaphorase, and in processes of the inner plexiform layer (IPL). sst 4 immunohistochemistry was found in ganglion cell bodies, where it was colocalized with NADPH-diaphorase, processes of the IPL and ganglion cell layer, and optic nerve fibers. sst 3 or sst 5 immunostain was not detected. Somatostatin increased NO production and this effect was mimicked only by the sst 2 specific analog L-779,976. The sst 2 antagonist CYN-154806 blocked the L-779,976 increase of NO production. These results present conclusive evidence that somatostatin's role in the retina involves the regulation of NO by an sst 2 mechanism.