Nivison-Smith Lisa, Zhu Yuan, Whatham Andrew, Bui Bang V, Fletcher Erica L, Acosta Monica L, Kalloniatis Michael
School of Optometry and Vision Science, UNSW Australia, Sydney, New South Wales, Australia.
School of Optometry and Vision Science, UNSW Australia, Sydney, New South Wales, Australia; Centre for Eye Health, Sydney, New South Wales, Australia.
Exp Eye Res. 2014 Nov;128:43-56. doi: 10.1016/j.exer.2014.08.014. Epub 2014 Sep 17.
Sildenafil, the active ingredient in Viagra, has been reported to cause transient visual disturbance from inhibition of phosphodiesterase 6 (PDE6), a key enzyme in the visual phototransduction pathway. This study investigated the effects of sildenafil on the rd1(+/-) mouse, a model for carriers of Retinitis Pigmentosa which exhibit normal vision but may have a lower threshold for cellular stress caused by sildenafil due to a heterozygous mutation in PDE6. Sildenafil caused a dose-dependent decrease in electroretinogram (ERG) responses of normal mice which mostly recovered two days post administration. In contrast, rd1(+/-) mice exhibited a significantly reduced photoreceptor and a supernormal bipolar cell response to sildenafil within 1 h of treatment. Carrier mice retinae took two weeks to return to baseline levels suggesting sildenafil has direct effects on both the inner and outer retina and these effects differ significantly between normal and carrier mice. Anatomically, an increase in expression of the early apoptotic marker, cytochrome C in rd1(+/-) mice indicated that the effects of sildenafil on visual function may lead to degeneration. The results of this study are significant considering approximately 1 in 50 people are likely to be carriers of recessive traits leading to retinal degeneration.
伟哥的活性成分西地那非据报道会因抑制磷酸二酯酶6（PDE6）而导致短暂性视觉障碍，PDE6是视觉光转导途径中的一种关键酶。本研究调查了西地那非对rd1（+/-）小鼠的影响，rd1（+/-）小鼠是视网膜色素变性携带者的模型，其视力正常，但由于PDE6中的杂合突变，可能对西地那非引起的细胞应激阈值较低。西地那非导致正常小鼠的视网膜电图（ERG）反应呈剂量依赖性降低，给药后两天大多恢复。相比之下，rd1（+/-）小鼠在治疗后1小时内对西地那非表现出明显降低的光感受器反应和超常的双极细胞反应。携带小鼠的视网膜需要两周时间才能恢复到基线水平，这表明西地那非对内视网膜和外视网膜都有直接影响，且这些影响在正常小鼠和携带小鼠之间有显著差异。从解剖学上看，rd1（+/-）小鼠早期凋亡标志物细胞色素C的表达增加，表明西地那非对视觉功能的影响可能导致退化。考虑到大约每50人中就有1人可能是导致视网膜退化的隐性性状携带者，本研究结果具有重要意义。
