sildenafil-citrate and alpha-cyano-4-hydroxycinnamate

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 Sprague-Dawley (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(+)-K(+)-ATPase and Mg(2+)-Ca(2+)-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 alpha-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.

Topics: Adenosine Triphosphate; Age Factors; Animals; Apoptosis; Ca(2+) Mg(2+)-ATPase; Coumaric Acids; Creatine; Creatine Kinase; Disease Models, Animal; Disease Progression; Energy Metabolism; Histidine; L-Lactate Dehydrogenase; Membrane Transport Proteins; Monocarboxylic Acid Transporters; Mutation; Phosphocreatine; Phosphodiesterase Inhibitors; Piperazines; Proline; Purines; Rats; Rats, Sprague-Dawley; Rats, Transgenic; Retina; Retinitis Pigmentosa; Sensory Rhodopsins; Sildenafil Citrate; Sodium-Potassium-Exchanging ATPase; Sulfones