Saeid Sama, Vinberg Frans, Koskelainen Ari
Department of Neuroscience and Biomedical Engineering, Aalto University, Espoo, Finland.
John A. Moran Eye Center, University of Utah, Salt Lake City, Utah, United States.
Invest Ophthalmol Vis Sci. 2025 Jun 2;66(6):14. doi: 10.1167/iovs.66.6.14.
This study investigates whether avanafil, a second-generation phosphodiesterase 5 (PDE5) inhibitor, exhibits reduced off-target effects on retinal function compared to first-generation inhibitors, by quantifying its impact on photoreceptor and bipolar cell signaling using transretinal electroretinography (tERG).
We conducted ex vivo tERG using wild-type C57BL/6J and Gnat-/- mice. The dark-adapted isolated retinas were stimulated with 530-nm full-field flashes of light while perfused with controlled avanafil concentrations at 0.1, 0.3, 1, 3, and 10 µM. The inhibition constant of avanafil for light-activated phosphodiesterase 6 (PDE6) was determined from flash responses for rods and cones. The effects of avanafil on bipolar cell signaling were also assessed.
Avanafil exhibited dose-dependent inhibition of rod and cone phototransduction, characterized by slower response kinetics and reduced amplitude of dim flash responses. The inhibition constants for light-activated PDE6 were determined to be 1.74 µM for rods and 6.3 µM for cones. This study demonstrated that avanafil does not inhibit spontaneous PDE6 activity, and it has a lower inhibitory effect on light-activated PDE6 compared to other PDE5 inhibitors like sildenafil and zaprinast. Additionally, we conclude that avanafil primarily impacts photoreceptor cells, with no significant direct effect on rod bipolar cell signaling.
This study provides quantitative insights into avanafil's impact on retinal function, supporting the hypothesis that it has reduced off-target effects on PDE6 and retinal signaling.
本研究通过使用经视网膜视网膜电图（tERG）量化第二代磷酸二酯酶5（PDE5）抑制剂阿伐那非对光感受器和双极细胞信号传导的影响，来探究其与第一代抑制剂相比是否对视网膜功能的脱靶效应更低。
我们使用野生型C57BL/6J和Gnat-/-小鼠进行了离体tERG实验。在以0.1、0.3、1、3和10 μM的可控阿伐那非浓度灌注的同时，用530纳米的全视野闪光刺激暗适应的离体视网膜。根据视杆和视锥细胞的闪光反应确定阿伐那非对光激活磷酸二酯酶6（PDE6）的抑制常数。还评估了阿伐那非对双极细胞信号传导的影响。
阿伐那非对视杆和视锥细胞的光转导表现出剂量依赖性抑制，其特征为反应动力学较慢和暗闪光反应幅度降低。光激活PDE6的抑制常数经测定，视杆细胞为1.74 μM，视锥细胞为6.3 μM。本研究表明，阿伐那非不抑制PDE6的自发活性，与西地那非和扎普司特等其他PDE5抑制剂相比，它对光激活PDE6的抑制作用更低。此外，我们得出结论，阿伐那非主要影响光感受器细胞，对视杆双极细胞信号传导无明显直接影响。
本研究提供了关于阿伐那非对视网膜功能影响的定量见解，支持了其对PDE6和视网膜信号传导的脱靶效应降低的假设。
