Nitric Oxide (NO): An emerging target for the treatment of glaucoma

Investigative Ophthalmology and Visual Science

Volumn 55, Issue 8, 2014, Pages 5005-5015

  Cavet, Megan E ^a   Vittitow, Jason L ^a   Impagnatiello, Francesco ^b   Ongini, Ennio ^b   Bastia, Elena ^b  

^a BAUSCH AND LOMB   (United States)

^b NicOx Research Institute   (Italy)

Author keywords

Aqueous outflow; Intraocular pressure; Nitric oxide

Indexed keywords

AQUEOUS OUTFLOW; INTRAOCULAR PRESSURE; NITRIC OXIDE;

ANIMALS; AQUEOUS HUMOR; ENDOTHELIUM-DEPENDENT RELAXING FACTORS; GLAUCOMA; HUMANS; INTRAOCULAR PRESSURE; NITRIC OXIDE; OXIDATIVE STRESS;

EID: 84906057370     PISSN: 01460404     EISSN: 15525783     Source Type: Journal    
DOI: 10.1167/iovs.14-14515     Document Type: Review

References (152)

1. Furchgott RF, Zawadzki JV. The obligatory role of endothelial cells in the relaxation of arterial smooth muscle by acetylcholine. Nature. 1980;288:373-376.
2. Palmer RM, Ferrige AG, Moncada S. Nitric oxide release accounts for the biological activity of endothelium-derived relaxing factor. Nature. 1987;327:524-526.
3. Moncada S, Higgs A, Furchgott R. International Union of Pharmacology Nomenclature in Nitric Oxide Research. Pharmacol Rev. 1997;49:137-142.
4. Boo YC, Jo H. Flow-dependent regulation of endothelial nitric oxide synthase: role of protein kinases. Am J Physiol Cell Physiol. 2003;285:C499-C508.
5. Handy DE, Loscalzo J. Nitric oxide and posttranslational modification of the vascular proteome: S-nitrosation of reactive thiols. Arterioscler Thromb Vasc Biol. 2006;26: 1207-1214.
6. Colasanti M, Suzuki H. The dual personality of NO. Trends Pharmacol Sci. 2000;21:249-252.
7. Hara MR, Agrawal N, Kim SF, et al. S-nitrosylated GAPDH initiates apoptotic cell death by nuclear translocation following Siah1 binding. Nat Cell Biol. 2005;7:665-674.
8. Becquet F, Courtois Y, Goureau O. Nitric oxide in the eye: multifaceted roles and diverse outcomes. Surv Ophthalmol. 1997;42:71-82.
9. Pacher P, Beckman JS, Liaudet L. Nitric oxide and peroxynitrite in health and disease. Physiol Rev. 2007;87:315-424.
10. Goldstein IM, Ostwald P, Roth S. Nitric oxide: a review of its role in retinal function and disease. Vision Res. 1996;36: 2979-2994.
11. Bryan NS, Bian K, Murad F. Discovery of the nitric oxide signaling pathway and targets for drug development. Front Biosci. 2009;14:1-18.
12. Kuo PC, Schroeder RA. The emerging multifaceted roles of nitric oxide. Ann Surg. 1995;221:220-235.
13. Moncada S. Nitric oxide in the vasculature: physiology and pathophysiology. Ann N Y Acad Sci. 1997;811:60-67, discussion 67-69.
14. Stewart AG, Phan LH, Grigoriadis G. Physiological and pathophysiological roles of nitric oxide. Microsurgery. 1994;15:693-702.
15. Thomas DD, Ridnour LA, Isenberg JS, et al. The chemical biology of nitric oxide: implications in cellular signaling. Free Rad Biol Med. 2008;45:18-31.
16. Chiou SH, Chang CJ, Hsu WM, et al. Elevated nitric oxide level in aqueous humor of patients with acute angle-closure glaucoma. Ophthalmologica. 2001;215:113-116.
17. Toda N, Nakanishi-Toda M. Nitric oxide: ocular blood flow, glaucoma, and diabetic retinopathy. Prog Retin Eye Res. 2007;26:205-238.
18. Sommer A. Intraocular pressure and glaucoma. Am J Ophthalmol. 1989;107:186-188.
19. Kass MA, Heuer DK, Higginbotham EJ, et al. The Ocular Hypertension Treatment Study: a randomized trial determines that topical ocular hypotensive medication delays or prevents the onset of primary open-angle glaucoma. Arch Ophthalmol. 2002;120:701-713.
20. Buys ES, Ko YC, Alt C, et al. Soluble guanylate cyclase alpha1-deficient mice: a novel murine model for primary open angle glaucoma. PLoS One. 2013;8:e60156.
21. Heyne GW, Kiland JA, Kaufman PL, Gabelt BT. Effect of nitric oxide on anterior segment physiology in monkeys. Invest Ophthalmol Vis Sci. 2013;54:5103-5110.
22. Stamer WD, Lei Y, Boussommier-Calleja A, Overby DR, Ethier CR. eNOS, a pressure-dependent regulator of intraocular pressure. Invest Ophthalmol Vis Sci. 2011;52:9438-9444.
23. Alm A, Nilsson SF. Uveoscleral outflow-a review. Exp Eye Res. 2009;88:760-768.
24. Wan Z, Woodward DF, Stamer WD. Endogenous bioactive lipids and the regulation of conventional outflow facility. Expert Rev Ophthalmol. 2008;3:457-470.
25. Nathanson JA, McKee M. Identification of an extensive system of nitric oxide-producing cells in the ciliary muscle and outflow pathway of the human eye. Invest Ophthalmol Vis Sci. 1995;36:1765-1773.
26. Chen HB, Yamabayashi S, Ou B, Tanaka Y, Ohno S, Tsukahara S. Histochemical study on rat tear film and ocular surface epithelial cells. Curr Eye Res. 1998;17:642-649.
27. Osborne NN, Barnett NL, Herrera AJ. NADPH diaphorase localization and nitric oxide synthetase activity in the retina and anterior uvea of the rabbit eye. Brain Res. 1993;610: 194-198.
28. Schneemann A, Leusink-Muis A, van den Berg T, Hoyng PF, Kamphuis W. Elevation of nitric oxide production in human trabecular meshwork by increased pressure. Graefes Arch Clin Exp Ophthalmol. 2003;241:321-326.
29. Haufschild T, Tschudi MR, Flammer J, Luscher TF, Haefliger IO. Nitric oxide production by isolated human and porcine ciliary processes. Graefes Arch Clin Exp Ophthalmol. 2000; 238:448-453.
30. Schneemann A, Dijkstra BG, van den Berg TJ, Kamphuis W, Hoyng PF. Nitric oxide/guanylate cyclase pathways and flow in anterior segment perfusion. Graefes Arch Clin Exp Ophthalmol. 2002;240:936-941.
31. Wiederholt M, Sturm A, Lepple-Wienhues A. Relaxation of trabecular meshwork and ciliary muscle by release of nitric oxide. Invest Ophthalmol Vis Sci. 1994;35:2515-2520.
32. Gabelt BT, Kaufman PL, Rasmussen CA. Effect of nitric oxide compounds on monkey ciliary muscle in vitro. Exp Eye Res. 2011;93:321-327.
33. Pianka P, Oron Y, Lazar M, Geyer O. Nonadrenergic, noncholinergic relaxation of bovine iris sphincter: role of endogenous nitric oxide. Invest Ophthalmol Vis Sci. 2000; 41:880-886.
34. Chuman H, Chuman T, Nao-i N, et al. Different responsiveness to nitric oxide-cyclic guanosine monophosphate pathway in cholinergic and tachykinergic contractions of the rabbit iris sphincter muscle. Invest Ophthalmol Vis Sci. 1997; 38:1719-1725.
35. Chuman T, Chuman H, Nao-i N, Sawada A, Yamamoto R, Wada A. Nitric oxide-sensitive and-insensitive contractions of the isolated rabbit iris sphincter muscle. Invest Ophthalmol Vis Sci. 1996;37:1437-1443.
36. Ellis DZ, Sharif NA, Dismuke WM. Endogenous regulation of human Schlemm's canal cell volume by nitric oxide signaling. Invest Ophthalmol Vis Sci. 2010;51:5817-5824.
37. Nathanson JA, McKee M. Alterations of ocular nitric oxide synthase in human glaucoma. Invest Ophthalmol Vis Sci. 1995;36:1774-1784.
38. Doganay S, Evereklioglu C, Turkoz Y, Er H. Decreased nitric oxide production in primary open-angle glaucoma. Eur J Ophthalmol. 2002;12:44-48.
39. Galassi F, Renieri G, Sodi A, Ucci F, Vannozzi L, Masini E. Nitric oxide proxies and ocular perfusion pressure in primary open angle glaucoma. Br J Ophthalmol. 2004;88:757-760.
40. Carter-Dawson L, Crawford ML, Harwerth RS, et al. Vitreal glutamate concentration in monkeys with experimental glaucoma. Invest Ophthalmol Vis Sci. 2002;43:2633-2637.
41. Hannappel E, Pankow G, Grassl F, Brand K, Naumann GO. Amino acid pattern in human aqueous humor of patients with senile cataract and primary open-angle glaucoma. Ophthalmic Res. 1985;17:341-343.
42. Kang JH, Wiggs JL, Rosner BA, et al. Endothelial nitric oxide synthase gene variants and primary open-angle glaucoma: interactions with sex and postmenopausal hormone use. Invest Ophthalmol Vis Sci. 2010;51:971-979.
43. Magalhaes DS, Rocha AV, Lacchini R, et al. Association of polymorphisms of endothelial nitric oxide synthase (eNOS) gene with the risk of primary open angle glaucoma in a Brazilian population. Gene. 2012;502:142-146.
44. Weiss J, Frankl SA, Flammer J, et al. No difference in genotype frequencies of polymorphisms of the nitric oxide pathway between Caucasian normal and high tension glaucoma patients. Mol Vis. 2012;18:2174-2181.
45. Nathanson JA. Nitrovasodilators as a new class of ocular hypotensive agents. J Pharmacol Exp Ther. 1992;260:956-965.
46. Kotikoski H, Alajuuma P, Moilanen E, et al. Comparison of nitric oxide donors in lowering intraocular pressure in rabbits: role of cyclic GMP. J Ocul Pharmacol Ther. 2002; 18:11-23.
47. Behar-Cohen FF, Goureau O, D'Hermies F, Courtois Y. Decreased intraocular pressure induced by nitric oxide donors is correlated to nitrite production in the rabbit eye. Invest Ophthalmol Vis Sci. 1996;37:1711-1715.
48. Carreiro S, Anderson S, Gukasyan HJ, Krauss A, Prasanna G. Correlation of in vitro and in vivo kinetics of nitric oxide donors in ocular tissues. J Ocul Pharmacol Ther. 2009;25: 105-112.
49. Schuman JS, Erickson K, Nathanson JA. Nitrovasodilator effects on intraocular pressure and outflow facility in monkeys. Exp Eye Res. 1994;58:99-105.
50. Wang RF, Podos SM. Effect of the topical application of nitroglycerin on intraocular pressure in normal and glaucomatous monkeys. Exp Eye Res. 1995;60:337-339.
51. Sugiyama T, Kida T, Mizuno K, Kojima S, Ikeda T. Involvement of nitric oxide in the ocular hypotensive action of nipradilol. Curr Eye Res. 2001;23:346-351.
52. Orihashi M, Shima Y, Tsuneki H, Kimura I. Potent reduction of intraocular pressure by nipradilol plus latanoprost in ocular hypertensive rabbits. Biol Pharm Bull. 2005;28:65-68.
53. Borghi V, Bastia E, Guzzetta M, et al. A novel nitric oxide releasing prostaglandin analog, NCX 125, reduces intraocular pressure in rabbit, dog, and primate models of glaucoma. J Ocul Pharmacol Ther. 2010;26:125-132.
54. Impagnatiello F, Borghi V, Gale DC, et al. A dual acting compound with latanoprost amide and nitric oxide releasing properties, shows ocular hypotensive effects in rabbits and dogs. Exp Eye Res. 2011;93:243-249.
55. Krauss AH, Impagnatiello F, Toris CB, et al. Ocular hypotensive activity of BOL-303259-X, a nitric oxide donating prostaglandin F2alpha agonist, in preclinical models. Exp Eye Res. 2011;93:250-255.
56. Wizemann AJ, Wizemann V. Organic nitrate therapy in glaucoma. Am J Ophthalmol. 1980;90:106-109.
57. Diestelhorst M, Hinzpeter B, Krieglstein GK. The effect of isosorbide-mononitrate eye drops on the human intraocular pressure and aqueous humor dynamics. Int Ophthalmol. 1991;15:259-262.
58. Chuman H, Chuman T, Nao-i N, Sawada A. The effect of Larginine on intraocular pressure in the human eye. Curr Eye Res. 2000;20:511-516.
59. Inoue K, Noguchi K, Wakakura M, Tomita G. Effect of five years of treatment with nipradilol eye drops in patients with normal tension glaucoma. Clin Ophthalmol. 2011;5:1211-1216.
60. Kanno M, Araie M, Koibuchi H, Masuda K. Effects of topical nipradilol, a beta blocking agent with alpha blocking and nitroglycerin-like activities, on intraocular pressure and aqueous dynamics in humans. Br J Ophthalmol. 2000;84: 293-299.
61. Eveleth D, Starita C, Tressler CA. 4-week, dose-ranging study comparing the efficacy, safety and tolerability of latanoprost 75, 100 and 125 mug/mL to latanoprost 50 mug/mL (xalatan) in the treatment of primary open-angle glaucoma and ocular hypertension. BMC Ophthalmol. 2012;12:9.
62. Sambhara D, Aref AA. Glaucoma management: relative value and place in therapy of available drug treatments. Ther Adv Chronic Dis. 2014;5:30-43.
63. Kee C, Kaufman PL, Gabelt BT. Effect of 8-Br cGMP on aqueous humor dynamics in monkeys. Invest Ophthalmol Vis Sci. 1994;35:2769-2773.
64. Kotikoski H, Vapaatalo H, Oksala O. Nitric oxide and cyclic GMP enhance aqueous humor outflow facility in rabbits. Curr Eye Res. 2003;26:119-123.
65. Ellis DZ, Dismuke WM, Chokshi BM. Characterization of soluble guanylate cyclase in NO-induced increases in aqueous humor outflow facility and in the trabecular meshwork. Invest Ophthalmol Vis Sci. 2009;50:1808-1813.
66. Dismuke WM, Mbadugha CC, Ellis DZ. NO-induced regulation of human trabecular meshwork cell volume and aqueous humor outflow facility involve the BKCa ion channel. Am J Physiol Cell Physiol. 2008;294:C1378-C1386.
67. Arnal JF, Dinh-Xuan AT, Pueyo M, Darblade B, Rami J. Endothelium-derived nitric oxide and vascular physiology and pathology. Cell Mol Life Sci. 1999;55:1078-1087.
68. Bolz SS, Vogel L, Sollinger D, et al. Nitric oxide-induced decrease in calcium sensitivity of resistance arteries is attributable to activation of the myosin light chain phosphatase and antagonized by the RhoA/Rho kinase pathway. Circulation. 2003;107:3081-3087.
69. Etter EF, Eto M, Wardle RL, Brautigan DL, Murphy RA. Activation of myosin light chain phosphatase in intact arterial smooth muscle during nitric oxide-induced relaxation. J Biol Chem. 2001;276:34681-34685.
70. Sauzeau V, Le Jeune H, Cario-Toumaniantz C, et al. Cyclic GMP-dependent protein kinase signaling pathway inhibits RhoA-induced Ca2{thorn} sensitization of contraction in vascular smooth muscle. J Biol Chem. 2000;275:21722-21729.
71. Thoonen R, Sips PY, Bloch KD, Buys ES. Pathophysiology of hypertension in the absence of nitric oxide/cyclic GMP signaling. Curr Hypertens Rep. 2013;15:47-58.
72. Ramachandran C, Patil RV, Combrink K, Sharif NA, Srinivas SP. Rho-Rho kinase pathway in the actomyosin contraction and cell-matrix adhesion in immortalized human trabecular meshwork cells. Mol Vis. 2011;17:1877-1890.
73. Rao PV, Deng P, Maddala R, Epstein DL, Li CY, Shimokawa H. Expression of dominant negative Rho-binding domain of Rhokinase in organ cultured human eye anterior segments increases aqueous humor outflow. Mol Vis. 2005;11:288-297.
74. Wang JW, Woodward DF, Stamer WD. Differential effects of prostaglandin E2-sensitive receptors on contractility of human ocular cells that regulate conventional outflow. Invest Ophthalmol Vis Sci. 2013;54:4782-4790.
75. Pattabiraman PP, Pecen PE, Rao PV. MRP4-mediated regulation of intracellular cAMP and cGMP levels in trabecular meshwork cells and homeostasis of intraocular pressure. Invest Ophthalmol Vis Sci. 2013;54:1636-1649.
76. Dismuke WM, Liang J, Overby DR, Stamer WD. Concentration-related effects of nitric oxide and endothelin-1 on human trabecular meshwork cell contractility. Exp Eye Res. 2013; 120C:28-35.
77. Goel M, Picciani RG, Lee RK, Bhattacharya SK. Aqueous humor dynamics: a review. Open Ophthalmol J. 2010;4:52-59.
78. Kameda T, Inoue T, Inatani M, et al. The effect of Rhoassociated protein kinase inhibitor on monkey Schlemm's canal endothelial cells. Invest Ophthalmol Vis Sci. 2012;53: 3092-3103.
79. Tousoulis D, Androulakis E, Papageorgiou N, Stefanadis C. Novel therapeutic strategies in the management of arterial hypertension. Pharmacol Ther. 2012;135:168-175.
80. Krupin T, Weiss A, Becker B, Holmberg N, Fritz C. Increased intraocular pressure following topical azide or nitroprusside. Invest Ophthalmol Vis Sci. 1977;16:1002-1007.
81. Zamora DO, Kiel JW. Episcleral venous pressure responses to topical nitroprusside and N-Nitro-L-arginine methyl ester. Invest Ophthalmol Vis Sci. 2010;51:1614-1620.
82. Funk RH, Gehr J, Rohen JW. Short-term hemodynamic changes in episcleral arteriovenous anastomoses correlate with venous pressure and IOP changes in the albino rabbit. Curr Eye Res. 1996;15:87-93.
83. Millar JC, Shahidullah M, Wilson WS. Intraocular pressure and vascular effects of sodium azide in bovine perfused eye. J Ocul Pharmacol Ther. 2001;17:225-234.
84. Shahidullah M, Yap M, To CH. Cyclic GMP sodium nitroprusside and sodium azide reduce aqueous humour formation in the isolated arterially perfused pig eye. Br J Pharmacol. 2005;145:84-92.
85. Miller TL, Willis AM, Wilkie DA, Hoshaw-Woodard S, Stanley JR. Description of ciliary body anatomy and identification of sites for transscleral cyclophotocoagulation in the equine eye. Vet Ophthalmol. 2001;4:183-190.
86. Ellis DZ, Nathanson JA, Rabe J, Sweadner KJ. Carbachol and nitric oxide inhibition of Na, K-ATPase activity in bovine ciliary processes. Invest Ophthalmol Vis Sci. 2001;42:2625-2631.
87. Shahidullah M, Delamere NA. NO donors inhibit Na, K-ATPase activity by a protein kinase G-dependent mechanism in the nonpigmented ciliary epithelium of the porcine eye. Br J Pharmacol. 2006;148:871-880.
88. Shahidullah M, Wei G, Delamere NA. DIDS inhibits Na-KATPase activity in porcine nonpigmented ciliary epithelial cells by a Src family kinase-dependent mechanism. Am J Physiol Cell Physiol. 2013;305:C492-C501.
89. Fleischhauer JC, Beny JL, Flammer J, Haefliger IO. NO/cGMP pathway activation and membrane potential depolarization in pig ciliary epithelium. Invest Ophthalmol Vis Sci. 2000;41: 1759-1763.
90. Wu R, Yao K, Flammer J, Haefliger IO. Role of anions in nitric oxide-induced short-circuit current increase in isolated porcine ciliary processes. Invest Ophthalmol Vis Sci. 2004; 45:3213-3222.
91. Johnson EC, Morrison JC. Friend or foe? Resolving the impact of glial responses in glaucoma. J Glaucoma. 2009;18:341-353.
92. Neufeld AH, Hernandez MR, Gonzalez M. Nitric oxide synthase in the human glaucomatous optic nerve head. Arch Ophthalmol. 1997;115:497-503.
93. Neufeld AH, Kawai S, Das S, et al. Loss of retinal ganglion cells following retinal ischemia: the role of inducible nitric oxide synthase. Exp Eye Res. 2002;75:521-528.
94. Shareef S, Sawada A, Neufeld AH. Isoforms of nitric oxide synthase in the optic nerves of rat eyes with chronic moderately elevated intraocular pressure. Invest Ophthalmol Vis Sci. 1999;40:2884-2891.
95. Neufeld AH, Das S, Vora S, et al. A prodrug of a selective inhibitor of inducible nitric oxide synthase is neuroprotective in the rat model of glaucoma. J Glaucoma. 2002;11:221-225.
96. Neufeld AH, Sawada A, Becker B. Inhibition of nitric-oxide synthase 2 by aminoguanidine provides neuroprotection of retinal ganglion cells in a rat model of chronic glaucoma. Proc Natl Acad Sci U S A. 1999;96:9944-9948.
97. Flammer J, Mozaffarieh M. What is the present pathogenetic concept of glaucomatous optic neuropathy? Surv Ophthalmol. 2007;52(suppl 2):S162-S173.
98. Pang IH, Johnson EC, Jia L, et al. Evaluation of inducible nitric oxide synthase in glaucomatous optic neuropathy and pressure-induced optic nerve damage. Invest Ophthalmol Vis Sci. 2005;46:1313-1321.
99. Libby RT, Howell GR, Pang IH, et al. Inducible nitric oxide synthase, Nos2, does not mediate optic neuropathy and retinopathy in the DBA/2J glaucoma model. BMC Neurosci. 2007;8:108.
100. Chen C, Xu Y, Zhang J, et al. Altered expression of nNOS/ NIDD in the retina of a glaucoma model of DBA/2J mice and the intervention by nNOS inhibition. J Mol Neurosci. 2013; 51:47-56.
101. Karim MZ, Sawada A, Mizuno K, Kawakami H, Ishida K, Yamamoto T. Neuroprotective effect of nipradilol [3,4-dihydro-8-(2-hydroxy-3-isopropylamino)-propoxy-3-nitroxy-2H-1-benzopyran] in a rat model of optic nerve degeneration. J Glaucoma. 2009;18:26-31.
102. Mizuno K, Koide T, Shimada S, Mori J, Sawanobori K, Araie M. Route of penetration of topically instilled nipradilol into the ipsilateral posterior retina. Invest Ophthalmol Vis Sci. 2009; 50:2839-2847.
103. Mizuno K, Koide T, Yoshimura M, Araie M. Neuroprotective effect and intraocular penetration of nipradilol, a betablocker with nitric oxide donative action. Invest Ophthalmol Vis Sci. 2001;42:688-694.
104. Watanabe M, Tokita Y, Yata T. Axonal regeneration of cat retinal ganglion cells is promoted by nipradilol, an antiglaucoma drug. Neuroscience. 2006;140:517-528.
105. Kitaoka Y, Kumai T, Isenoumi K, et al. Neuroprotective effect of nitric oxide against NMDA-induced neurotoxicity in the rat retina is associated with tyrosine hydroxylase expression. Brain Res. 2003;977:46-54.
106. Zurakowski D, Vorwerk CK, Gorla M, et al. Nitrate therapy may retard glaucomatous optic neuropathy, perhaps through modulation of glutamate receptors. Vision Res. 1998;38: 1489-1494.
107. Takahata K, Katsuki H, Kume T, et al. Retinal neuronal death induced by intraocular administration of a nitric oxide donor and its rescue by neurotrophic factors in rats. Invest Ophthalmol Vis Sci. 2003;44:1760-1766.
108. Kashii S, Mandai M, Kikuchi M, et al. Dual actions of nitric oxide in N-methyl-D-aspartate receptor-mediated neurotoxicity in cultured retinal neurons. Brain Res. 1996;711:93-101.
109. Kashiwagi K, Iizuka Y, Tanaka Y, et al. Dual action of nitric oxide on purely isolated retinal ganglion cells. Curr Eye Res. 2001;23:233-239.
110. Koriyama Y, Kamiya M, Takadera T, et al. Protective action of nipradilol mediated through S-nitrosylation of Keap1 and HO-1 induction in retinal ganglion cells. Neurochem Int. 2012; 61:1242-1253.
111. Koriyama Y, Kamiya M, Arai K, Sugitani K, Ogai K, Kato S. Nipradilol promotes axon regeneration through S-nitrosylation of PTEN in retinal ganglion cells. Adv Exp Med Biol. 2014;801:751-757.
112. Wenk GL, McGann-Gramling K, Hauss-Wegrzyniak B, et al. Attenuation of chronic neuroinflammation by a nitric oxidereleasing derivative of the antioxidant ferulic acid. J Neurochem. 2004;89:484-493.
113. Ronchetti D, Impagnatiello F, Guzzetta M, et al. Modulation of iNOS expression by a nitric oxide-releasing derivative of the natural antioxidant ferulic acid in activated RAW 264.7 macrophages. Eur J Pharmacol. 2006;532:162-169.
114. Katsuyama K, Shichiri M, Marumo F, Hirata Y. NO inhibits cytokine-induced iNOS expression and NF-kappaB activation by interfering with phosphorylation and degradation of IkappaB-alpha. Arterioscler Thromb Vasc Biol. 1998;18: 1796-1802.
115. Cavicchi M, Gibbs L, Whittle BJ. Inhibition of inducible nitric oxide synthase in the human intestinal epithelial cell line, DLD-1, by the inducers of heme oxygenase 1, bismuth salts, heme, and nitric oxide donors. Gut. 2000;47:771-778.
116. Findl O, Rainer G, Dallinger S, et al. Assessment of optic disk blood flow in patients with open-angle glaucoma. Am J Ophthalmol. 2000;130:589-596.
117. Michelson G, Langhans MJ, Harazny J, Dichtl A. Visual field defect and perfusion of the juxtapapillary retina and the neuroretinal rim area in primary open-angle glaucoma. Graefes Arch Clin Exp Ophthalmol. 1998;236:80-85.
118. Grunwald JE, Piltz J, Hariprasad SM, DuPont J. Optic nerve and choroidal circulation in glaucoma. Invest Ophthalmol Vis Sci. 1998;39:2329-2336.
119. Flammer J. The vascular concept of glaucoma. Surv Ophthalmol. 1994;38(suppl):S3-S6.
120. Flammer J, Orgul S. Optic nerve blood-flow abnormalities in glaucoma. Prog Retin Eye Res. 1998;17:267-289.
121. Haefliger IO, Flammer J, Beny JL, Luscher TF. Endotheliumdependent vasoactive modulation in the ophthalmic circulation. Prog Retin Eye Res. 2001;20:209-225.
122. Chen Z, Gu Q, Kaufman PL, Cynader MS. Histochemical mapping of NADPH-diaphorase in monkey and human eyes. Curr Eye Res. 1998;17:370-379.
123. Hashitani H, Windle A, Suzuki H. Neuroeffector transmission in arterioles of the guinea-pig choroid. J Physiol. 1998;510(pt 1):209-223.
124. Yamamoto R, Bredt DS, Snyder SH, Stone RA. The localization of nitric oxide synthase in the rat eye and related cranial ganglia. Neuroscience. 1993;54:189-200.
125. Haefliger IO, Flammer J, Luscher TF. Nitric oxide and endothelin-1 are important regulators of human ophthalmic artery. Invest Ophthalmol Vis Sci. 1992;33:2340-2343.
126. Yao K, Tschudi M, Flammer J, Luscher TF. Endotheliumdependent regulation of vascular tone of the porcine ophthalmic artery. Invest Ophthalmol Vis Sci. 1991;32: 1791-1798.
127. Benedito S, Prieto D, Nielsen PJ, Nyborg NC. Role of the endothelium in acetylcholine-induced relaxation and spontaneous tone of bovine isolated retinal small arteries. Exp Eye Res. 1991;52:575-579.
128. Deussen A, Sonntag M, Vogel R. L-arginine-derived nitric oxide: a major determinant of uveal blood flow. Exp Eye Res. 1993;57:129-134.
129. Granstam E, Granstam SO, Fellstrom B, Lind L. Endotheliumdependent vasodilation in the uvea of hypertensive and normotensive rats. Curr Eye Res. 1998;17:189-196.
130. Seligsohn EE, Bill A. Effects of NG-nitro-L-arginine methyl ester on the cardiovascular system of the anaesthetized rabbit and on the cardiovascular response to thyrotropin-releasing hormone. Br J Pharmacol. 1993;109:1219-1225.
131. Jacot JL, O'Neill JT, Scandling DM, West SD, McKenzie JE. Nitric oxide modulation of retinal, choroidal, and anterior uveal blood flow in newborn piglets. J Ocul Pharmacol Ther. 1998;14:473-489.
132. Dorner GT, Garhofer G, Kiss B, et al. Nitric oxide regulates retinal vascular tone in humans. Am J Physiol Heart Circ Physiol. 2003;285:H631-H636.
133. Luksch A, Polak K, Beier C, et al. Effects of systemic NO synthase inhibition on choroidal and optic nerve head blood flow in healthy subjects. Invest Ophthalmol Vis Sci. 2000;41: 3080-3084.
134. Schmetterer L, Krejcy K, Kastner J, et al. The effect of systemic nitric oxide-synthase inhibition on ocular fundus pulsations in man. Exp Eye Res. 1997;64:305-312.
135. Polak K, Luksch A, Berisha F, Fuchsjaeger-Mayrl G, Dallinger S, Schmetterer L. Altered nitric oxide system in patients with open-angle glaucoma. Arch Ophthalmol. 2007;125:494-498.
136. Delaey C, Van de Voorde J. The effect of NO donors on bovine retinal small arteries and posterior ciliary arteries. Invest Ophthalmol Vis Sci. 1998;39:1642-1646.
137. Okamura T, Kitamura Y, Uchiyama M, Toda M, Ayajiki K, Toda N. Canine retinal arterial and arteriolar dilatation induced by nipradilol, a possible glaucoma therapeutic. Pharmacology. 1996;53:302-310.
138. Donati G, Pournaras CJ, Tsacopoulos M. Effect of nitroprusside on arteriolar constriction after retinal branch vein occlusion. Invest Ophthalmol Vis Sci. 1998;39:1910-1917.
139. Kitamura Y, Okamura T, Kani K, Toda N. Nitric oxidemediated retinal arteriolar and arterial dilatation induced by substance P. Invest Ophthalmol Vis Sci. 1993;34:2859-2865.
140. Ogawa N, Mori A, Hasebe M, et al. Nitric oxide dilates rat retinal blood vessels by cyclooxygenase-dependent mechanisms. Am J Physiol Regul Integr Comp Physiol. 2009;297: R968-R977.
141. Schmidl D, Polska E, Kiss B, Sacu S, Garhofer G, Schmetterer L. Ocular hemodynamic effects of nitrovasodilators in healthy subjects. Clin Pharmacol Ther. 2010;87:87-92.
142. Grunwald JE, Iannaccone A, DuPont J. Effect of isosorbide mononitrate on the human optic nerve and choroidal circulations. Br J Ophthalmol. 1999;83:162-167.
143. Iannaccone AE, DuPont J, Grunwald JE. Human retinal hemodynamics following administration of 5-isosorbide mononitrate. Curr Eye Res. 2000;20:205-210.
144. Kida T, Sugiyama T, Harino S, Kitanishi K, Ikeda T. The effect of nipradilol, an alpha-beta blocker, on retinal blood flow in healthy volunteers. Curr Eye Res. 2001;23:128-132.
145. Mizuno K, Koide T, Saito N, et al. Topical nipradilol: effects on optic nerve head circulation in humans and periocular distribution in monkeys. Invest Ophthalmol Vis Sci. 2002;43: 3243-3250.
146. Keeble JE, Moore PK. Pharmacology and potential therapeutic applications of nitric oxide-releasing non-steroidal anti-inflammatory and related nitric oxide-donating drugs. Br J Pharmacol. 2002;137:295-310.
147. Mariotto S, Suzuki Y, Persichini T, Colasanti M, Suzuki H, Cantoni O. Cross-talk between NO and arachidonic acid in inflammation. Curr Med Chem. 2007;14:1940-1944.
148. Guimaraes C, Assreuy J, Linden R. Paracrine neuroprotective effect of nitric oxide in the developing retina. J Neurochem. 2001;76:1233-1241.
149. Mejia-Garcia TA, Portugal CC, Encarnacao TG, Prado MA, Paes-de-Carvalho R. Nitric oxide regulates AKT phosphorylation and nuclear translocation in cultured retinal cells. Cell Signal. 2013;25:2424-2439.
150. Calabrese EJ. Nitric oxide: biphasic dose responses. Crit Rev Toxicol. 2001;31:489-501.
151. Stamer WD, Acott TS. Current understanding of conventional outflow dysfunction in glaucoma. Curr Opin Ophthalmol. 2012;23:135-143.
152. Toris CB, Yablonski ME, Wang YL, Camras CB. Aqueous humor dynamics in the aging human eye. Am J Ophthalmol. 1999;127:407-412.