Williams D S, Colley N J, Farber D B
Invest Ophthalmol Vis Sci. 1987 Jul;28(7):1059-69.
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.
先前的研究表明，磷酸二酯酶抑制剂和环核苷酸类似物破坏环核苷酸代谢会损害富含视杆细胞的视网膜中的光感受器。在这些研究中，只有在周围的视杆细胞开始退化后，视锥光感受器才出现损伤。我们的目的是测试在没有视杆光感受器的情况下，视锥光感受器是否易受类似处理的影响。我们在体外眼杯制备中处理纯视锥蜥蜴视网膜。10⁻³M而非10⁻⁵M的磷酸二酯酶抑制剂异丁基甲基黄嘌呤（IBMX）可诱导视锥细胞退化。在24℃下10小时后，视锥细胞外段形态的变化首次明显可见。暴露时间更长后，其他视网膜细胞也受到影响。在形态受到影响之前，整个视网膜中所有分子量的蛋白质合成均受到抑制。此外，视网膜环磷酸腺苷（cAMP）和环磷酸鸟苷（cGMP）水平均升高，尤其是在2 - 10小时后。10⁻³M IBMX对所有这些参数的影响在10小时后通过从IBMX中移除仍可逆转。10⁻²M的二丁酰环磷酸腺苷也抑制蛋白质合成。它也诱导退化，但比10⁻³M IBMX慢。二丁酰环磷酸鸟苷（10⁻²M）或丁酸对视锥细胞形态没有显著影响，也不抑制视网膜对³H - 亮氨酸的摄取或掺入。与10⁻³M IBMX抑制视网膜蛋白质合成量相同的嘌呤霉素或环己酰亚胺浓度对视锥细胞形态或环核苷酸水平没有影响。该浓度的一百倍在扰乱视锥细胞外段组织之前会诱导视网膜核层出现核固缩。总之，毫摩尔浓度的IBMX和二丁酰环磷酸腺苷即使在没有相邻视杆细胞的情况下也会损害视锥细胞，表明升高的环核苷酸水平本身对视锥细胞有毒性。环核苷酸的损伤水平也会抑制视网膜蛋白质合成，但它似乎不是视锥细胞结构退化的原因。
