both with NADPHd staining and NOS-selective antibodies (cf. Vaney and Young, 1988; Straznicky and Gabriel, 1991; Osborne et al., 1993; Weiler and Kewitz, 1993; Kurenni et al., 1995). Although there are significant differences among species (Fig. 4.16), NOS is expressed to a varying degree in the ellipsoids of photoreceptor inner segments, in every neuronal cell type of the inner nuclear layer, in ganglion cells, and notably, within Müller cells (Goureau et al., 1994b; Liepe et al., 1994; Darius et al., 1995; Huxlin, 1995; Kim et al., 1999). Interestingly, long before neuronal NADPHd activity was identified with NOS or associated with NO production, Toichiro Kuwabara, David Cogan, and their coworkers (Kuwabara et al., 1957; Cogan and Kuwabara, 1959) studying the retinal distribution of dehydrogenases reported that tetrazolium precipitate was present in human Müller cells under substrate conditions requiring activity of the diaphorase. In addition to cells of the neural retina, both human and bovine RPE cells produce NO in response to cytokines (Goureau et al., 1992, 1994a), a reaction that may result in inhibition of the important phagocytic activity performed by RPE cells (Becquet et al., 1994).

With so many potential sources of NO in the retina, questions arise as to which cellular functions are affected by NO, and which cells provide the NO that modulate these functions. Not surprisingly, the molecule has been implicated in a broad range of phenomena, including visual adaptation, modulation of gap junctions, and ischemic injury (reviewed by Goldstein et al., 1996). In isolated rod photoreceptors, for example, NO donors induce membrane depolarization in dark-adapted cells, and accelerate recovery of the dark current after photic stimulation (Schmidt et al., 1992; Tsuyama et al., 1993). Both reactions reflect changes in guanylate cyclase activity, cGMP production, and the opening of cGMP-gated cation channels. Activation of a cGMP-gated conductance by NO donors has been demonstrated also in ganglion (Ahmad et al., 1994) and bipolar cells (Shiells and Falk, 1992), and as illustrated in Fig. 4.17, agents that generate NO or activate endogenous guanylate cyclase close gap junction channels and significantly block electrical and dye coupling between horizontal cells (DeVries and Schwartz, 1989; Miyachi et al., 1991,1994; Pottek et al., 1997). The effect on gap-junctional coupling may vary with cell type, considering results obtained from recordings within rat supraoptic nucleus, where NO-induced cGMP production increased neuronal coupling (Yang and Hatton, 1999).

Clearly retinal cells which express NOS and contain soluble guanylyl cyclase may autoregulate their activity via NO. However, the NO directly responsible for mediating a physiological response in vivo also could reach its targets by diffusion from neighboring cells (cf. Vincent and Hope, 1992). As we have seen, Müller cells contribute to NO production in the retina of many vertebrates (Goureau et al., 1994b; Liepe et al., 1994; Darius et al.,

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