Sildenafil (Viagra) evokes retinal arteriolar dilation: dual pathways via NOS activation and phosphodiesterase inhibition.
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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 microm) dilated dose dependently to sildenafil (1 ng/mL to 1 microg/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 microM) 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.
Invest Ophthalmol Vis Sci
author list (cited authors)
Yuan, Z., Hein, T. W., Rosa, R. H., & Kuo, L.
complete list of authors
Yuan, Zhaoxu||Hein, Travis W||Rosa, Robert H||Kuo, Lih