Sildenafil (Viagra) evokes retinal arteriolar dilation: dual pathways via NOS activation and phosphodiesterase inhibition.
Sildenafil (Viagra) evokes retinal arteriolar dilation: dual pathways via NOS activation and phosphodiesterase inhibition.
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西地那非（伟哥）引起视网膜小动脉扩张：通过 NOS 激活和磷酸二酯酶抑制的双重途径。
DOI：
10.1167/iovs.07-1208
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发表时间：
2008
影响因子：
4.4
通讯作者：
Kuo,Lih
中科院分区：
文献类型：
--
作者：
Yuan,Zhaoxu;Hein,TravisW;RosaJr,RobertH;Kuo,Lih
目的。西地那非（Viagra; Pfizer, New York， NY）是一种选择性磷酸二酯酶5型（PDE5）抑制剂，通过提高cGMP改善阴茎血流量，被广泛用于治疗阳痿。然而，它对眼循环的影响是有争议的，视网膜小动脉是否对这种药物有反应尚不清楚。在本研究中，研究了视网膜小动脉对西地那非的直接反应，并探讨了这种血管舒缩活性的信号通路。分离猪眼视网膜小动脉，插管，加压，无血流。用视频显微技术记录了西地那非对内径的影响。西地那非（1 ng/mL ~ 1 μg/mL）使视网膜小动脉（67±2 μm）呈剂量依赖性扩张。一氧化氮（NO）合成酶抑制剂N - g -硝基-l-精氨酸甲酯（l-NAME）、冠酰环化酶抑制剂1H-[1,2,4] oxadiazolo [4,3 -a] quinoxalin-1-one （ODQ）、细胞外信号调节激酶（ERK）途径抑制剂PD98059、非选择性钾通道阻滞剂四乙基铵（TEA）和选择性三磷酸腺苷（ATP）敏感钾（K ATP）通道阻滞剂格列本脲可抑制这种扩张。一氧化氮供体s -亚硝基-n -乙酰青霉胺（SNAP）引起的血管舒张被ODQ和TEA抑制，但对PD98059不敏感。在l-NAME存在的情况下，添加SNAP （1 μM）产生适度的血管舒张，随后恢复了被抑制的西地那非反应。恢复的扩张对PD98059不敏感，但被tea阻断。通过ERK信号激活NO合成酶，导致NO的产生和随后的guanylyl环化酶激活和K ATP通道的打开是西地那非在视网膜小动脉中的主要血管扩张途径。此外，来自内源性或外源性NO的cGMP升高，通过抑制不依赖ERK信号的PDE5通路，为西地那非发挥血管舒张作用发挥了许可作用。
purpose. Sildenafil (Viagra; Pfizer, New York, NY), a selective phosphodiesterase type-5 (PDE5) inhibitor, is widely used to treat impotence by improving penile blood flow via elevation of cGMP. However, its effect on ocular circulation is controversial and whether retinal arterioles are responsive to this drug remains unclear. In this study, the direct reaction of retinal arterioles to sildenafil was examined and the signaling pathway underlying this vasomotor activity was probed.methods. Retinal arterioles from porcine eyes were isolated, cannulated, and pressurized without flow. Diameter changes in response to sildenafil were recorded using videomicroscopic techniques.results. Retinal arterioles (67±2 μm) dilated dose dependently to sildenafil (1 ng/mL to 1 μg/mL). This dilation was inhibited by the nitric oxide (NO) synthase inhibitor N G-nitro-l-arginine methyl ester (l-NAME), the guanylyl cyclase inhibitor 1H-[1, 2, 4] oxadiazolo [4, 3-a] quinoxalin-1-one (ODQ), the extracellular signal-regulated kinase (ERK) pathway inhibitor PD98059, the nonselective potassium channel blocker tetraethylammonium (TEA), and the selective adenosine triphosphate (ATP)-sensitive potassium (K ATP) channel blocker glibenclamide. The vasodilation elicited by the NO donor S-nitroso-N-acetylpenicillamine (SNAP) was inhibited by ODQ and TEA but was insensitive to PD98059. In the presence of l-NAME, the addition of SNAP (1 μM) produced modest vasodilation and the inhibited sildenafil response was subsequently restored. The restored dilation was insensitive to PD98059 but was blocked by TEA.conclusions. Activation of NO synthase, through ERK signaling, leading to NO production and subsequent guanylyl cyclase activation and K ATP channel opening is the major vasodilatory pathway for sildenafil in retinal arterioles. Moreover, the elevated cGMP, from endogenous or exogenous NO, plays a permissive role for sildenafil to exert vasodilation through inhibition of the PDE5 pathway independent of ERK signaling.