May 2007
Volume 48, Issue 13
Free
ARVO Annual Meeting Abstract  |   May 2007
Permissive Role of Endothelial Released Nitric Oxide in the Dilation of Retinal Arterioles to Sildenafil (Viagra)
Author Affiliations & Notes
  • Z. Yuan
    Ophthalmology, Scott & White Eye Institute, Temple, Texas
  • T. W. Hein
    Ophthalmology, Scott & White Eye Institute, Temple, Texas
  • R. H. Rosa
    Ophthalmology, Scott & White Eye Institute, Temple, Texas
  • L. Kuo
    Ophthalmology, Scott & White Eye Institute, Temple, Texas
  • Footnotes
    Commercial Relationships Z. Yuan, None; T.W. Hein, None; R.H. Rosa, None; L. Kuo, None.
  • Footnotes
    Support Scott & White Research Foundation Ophthalmic Vascular Research Program
Investigative Ophthalmology & Visual Science May 2007, Vol.48, 2258. doi:
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      Z. Yuan, T. W. Hein, R. H. Rosa, L. Kuo; Permissive Role of Endothelial Released Nitric Oxide in the Dilation of Retinal Arterioles to Sildenafil (Viagra). Invest. Ophthalmol. Vis. Sci. 2007;48(13):2258.

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      © ARVO (1962-2015); The Authors (2016-present)

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Abstract

Purpose:: Sildenafil (Viagra), a selective inhibitor of phosphodiesterase type-5 (PDE5), is widely used for the treatment of erectile dysfunction by increasing penile blood flow via elevated cGMP. Although sildenafil has been shown to increase retinal blood flow, its vasomotor action in the retinal arterial vasculature is controversial. Herein, we directly examined the response of small retinal arterioles to sildenafil and characterized the possible underlying signaling mechanisms.

Methods:: Small second-order retinal arterioles from porcine eye were isolated, cannulated, and pressurized to 55 cmH2O lumenal pressure without flow for functional study. Diameter changes in response to sildenafil were recorded using videomicroscopic techniques. Pharmacological tools were employed to probe signaling pathways.

Results:: Retinal arterioles developed basal tone (66±8 µm internal diameter) and dilated dose-dependently to sildenafil (0.01 to 1 µg/mL). This dilation was abolished by a nitric oxide synthase (NOS) inhibitor L-NAME (10 µM), soluble guanylyl cyclase inhibitor 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one (ODQ, 0.1 µM), mitogen-activated protein kinase (MAPK) inhibitor PD98059 (0.3 µM), and a non-selective potassium channel blocker tetraethylammonium (TEA, 20 mM). In the presence of L-NAME, the inhibited sildenafil response was not affected by providing the vessels with a basal level of cGMP from a low dose of NO donor S-nitroso-N-acetylpenicillamine (SNAP, 0.5 µM), but was reversed after treating the vessels with a higher dose of SNAP (1 µM). The vasodilation restored by SNAP was insensitive to MAPK inhibitor, but was blocked by ODQ or TEA.

Conclusions:: It appears that NOS activation, through MAPK signaling, and the subsequent NO production leading to guanylyl cyclase activation and opening of potassium channels is the major pathway involved in the sildenafil-induced vasodilation. Moreover, the elevated cGMP, by endogenous or exogenous NO, can play a permissive role for sildenafil-induced dilation through the inhibition of PDE5 in a MAPK-independent manner.

Keywords: nitric oxide • drug toxicity/drug effects • retina 
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