Photoreceptor degeneration in a pure-cone retina. Effects of cyclic nucleotides, and inhibitors of phosphodiesterase and protein synthesis.

Previous studies have shown that disruption of cyclic nucleotide metabolism by phosphodiesterase inhibitors and cyclic nucleotide analogues damages photoreceptors in rod-enriched retinae. In these studies the cone photoreceptors appeared damaged only after the surrounding rods had begun to degenerate. Our aim was to test if cone photoreceptors were susceptible to similar treatments in the absence of rod photoreceptors. We treated pure-cone lizard retinae in an in vitro eyecup preparation. Degeneration of the cones was induced by 10(-3) M, but not 10(-5) M, of the phosphodiesterase inhibitor, isobutylmethylxanthine (IBMX). Changes in the morphology of the cone outer segments were first evident after 10 hr at 24 degrees C. After longer exposures, other retinal cells were also affected. Before morphology was affected, synthesis of proteins of all molecular weights was inhibited throughout the retina. In addition, both retinal cyclic AMP and cyclic GMP levels were elevated, particularly after 2-10 hr. The effects of 10(-3) M IBMX on all of these parameters were still reversible by removal from IBMX after 10 hr. Dibutyryl cyclic AMP at 10(-2) M also inhibited protein synthesis. It also induced degeneration, but less rapidly than 10(-3) M IBMX. Dibutyryl cyclic GMP (10(-2) M) or butyric acid did not significantly affect morphology, or inhibit uptake or incorporation of 3H-leucine by retinae. The concentration of puromycin or cycloheximide that inhibited retinal protein synthesis by the same amount as 10(-3) M IBMX did not affect retinal morphology or cyclic nucleotide levels. One hundred times this concentration induced pyknosis in the nuclear layers of the retina before disturbing cone outer segment organization. In conclusion, millimolar IBMX and dibutyryl cyclic AMP damage cones even without neighboring rods, indicating that elevated cyclic nucleotide levels are toxic to cones per se. Retinal protein synthesis is also inhibited by damaging levels of cyclic nucleotides, but it does not seem to be responsible for the deterioration of cone structure.