-We determined the metabolic changes that precede cell death in the dystrophic proline-23-histidine (P23H) line 3 (P23H-3) rat retina compared with the normal SpragueDawley (SD) rat retina. Metabolite levels and metabolic enzymes were analyzed early in development and during the early stages of degeneration in the P23H-3 retina. Control and degenerating retinas showed an age-dependent change in metabolite levels and enzymatic activity, particularly around the time when phototransduction was activated. However, lactate dehydrogenase (LDH) activity was significantly higher in P23H-3 than SD retina before the onset of photoreceptor death. The creatine/phosphocreatine system did not contribute to the increase in ATP, because phosphocreatine levels, creatine kinase, and expression of the creatine transporter remained constant. However, Na ϩ -K ϩ -ATPase and Mg 2ϩ -Ca 2ϩ -ATPase activities were increased in the developing P23H-3 retina. Therefore, photoreceptor apoptosis in the P23H-3 retina occurs in an environment of increased LDH, ATPase activity, and higher-than-normal ATP levels. We tested the effect of metabolic challenge to the retina by inhibiting monocarboxylate transport with ␣-cyano-4-hydroxycinnamic acid or systemically administering the phosphodiesterase inhibitor sildenafil. Secondary to monocarboxylate transport inhibition, the P23H-3 retina did not demonstrate alterations in metabolic activity. However, administration of sildenafil significantly reduced LDH activity in the P23H-3 retina and increased the number of terminal deoxynucleotidyl transferase biotin-dUPT nick end-labeled photoreceptor cells. Photoreceptor cells with a rhodopsin mutation display an increase in apoptotic markers secondary to inhibition of a phototransduction enzyme (phosphodiesterase), suggesting increased susceptibility to altered cation entry.phosphocreatine; ATP; ␣-cyano-4-hydroxycinnamic acid; sildenafil; lactate dehydrogenase; ATPase RETINITIS PIGMENTOSA is the term given to a family of retinal disorders that cause blindness due to gradual loss of photoreceptors. Although photoreceptor cell death in retinitis pigmentosa has a number of underlying causes that include rhodopsin mutations (94), altered photoreceptor oxygen environment (36,103,104), disk morphogenesis, retinal pigment epithelium dysfunction, and chronic activation of photoreceptor transduction cascade (80), the understanding of the cell death pathways is still evolving. It is generally accepted that cell death in inherited forms of retinal degeneration occurs via the process of apoptosis (16,66,82,92), an active cellular process requiring energy (25). The concept of apoptosis as the major pathway of cell death in inherited forms of retinal degeneration has recently been questioned with a proposal that nonapoptotic pathways also contribute to photoreceptor death (7,23,42,63,86,107).Increased metabolic activity is a potential cause of photoreceptor death in some models of retinal dystrophy, such as the rd/rd (rd1) model, where cyclic nucleotide channels are malfu...