Early vascular insights and discoveries
Early vascular insights and discoveries
NITRIC OXIDE AND IOP
Nitric oxide and
CONVENTIONAL OUTFLOW
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Early vascular insights and discoveries

  • Nitric oxide molecule 1775
    First Discovery of NITRIC OXIDE

    Nitric oxide is discovered by English chemist Joseph Priestley.1

  • Heart 1860s
    NITRATES HARNESSED TO TREAT VASCULAR DISEASE

    T. Lauder Brunton and William Murrell pioneer the use of nitrates for the treatment of angina and hypertension.1

  • Nobel prize 1977-1987
    NITRIC OXIDE ESTABLISHED AS A KEY CARDIOVASCULAR SIGNALING MOLECULE

    Landmark research by Robert Furchgott, Louis Ignarro, and Ferid Murad establishes nitric oxide as the key effector of vascular smooth muscle cell relaxation, leading to the 1998 Nobel Prize in Physiology/Medicine.1

Nitric oxide and IOP

  • Oral nitrates 1980
    Systemic nitrates found to lower IOP

    Angelika and Volker Wizemann report that a short course of oral organic nitrates leads to a drop in IOP.4

  • Topical nitrovasodilator drop MARCH 1992
    Topical nitroglycerin shown to effectively lower IOP

    In a tonographic study of rabbit eyes, James Nathanson and colleagues are the first to suggest that topical nitrovasodilators may be effective ocular hypotensive agents for individuals with elevated IOP.5

  • Fireworks DECEMBER 1992
    NITRIC OXIDE NAMED "MOLECULE OF THE YEAR"

    Science proclaims nitric oxide the molecule of the year based on widespread recognition of its multitude of critical physiological functions throughout the body.6

  • Arrows 1994
    EXOGENOUS NITRIC OXIDE RELAXES THE TRABECULAR MESHWORK

    Exogenous nitric oxide is found to reduce outflow resistance within the trabecular meshwork (TM) and ciliary muscle of bovine eyes. The TM is postulated as a resistance system regulating outflow and modulated by “hormonal contractile and relaxing influences.”7

NITRIC OXIDE AND CONVENTIONAL OUTFLOW

  • Anterior eye 1995
    ANTERIOR EYE ENRICHED IN eNOS

    Nathanson and colleagues discover that endothelial nitric oxide synthase (eNOS) is constitutively expressed throughout Schlemm’s canal in the human conventional outflow pathway. Endogenous nitric oxide is hypothesized to play a key role in regulating outflow resistance.8

  • eNOS gene mutation 1998
    eNOS GENE MUTATIONS ASSOCIATED WITH ELEVATED POAG RISK

    Polymorphisms in the NOS3 gene are associated with primary open-angle glaucoma (POAG). This is later confirmed in large, population-based case-control studies.9,10

  • Nitric oxide markers 2002/2004
    NITRIC OXIDE MARKERS DEPLETED IN GLAUCOMATOUS EYES

    Two separate groups demonstrate that nitric oxide markers within aqueous humor are reduced by up to 40% in patients with glaucoma vs healthy controls.11,12

  • Transgenic mouse model 2011
    eNOS OVEREXPRESSION LOWERS IOP

    Utilizing an eNOS transgenic mouse model, Dan Stamer and colleagues demonstrate that eNOS overexpression within endothelial cells of the eye lowers IOP by increasing pressure-dependent outflow.13

  • Shear stress within Schlemm’s canal 2014
    SHEAR STRESS-TRIGGERED NITRIC OXIDE RESTORES IOP HOMEOSTASIS

    When IOP is elevated, shear stress within Schlemm’s canal triggers nitric oxide production. This physiologic signaling cascade mirrors that observed in maintenance of vascular tone.14

  • Nitrates in a green leaf 2016
    HIGH DIETARY NITRATE INTAKE ASSOCIATED WITH LOWER POAG RISK

    Among 1,483 patients with POAG, those with higher dietary intake of nitrates, primarily sourced through green leafy vegetables, demonstrate reduced risk level of both POAG and POAG subtypes.15

  • Dilated distal vessel 2018
    NITRIC OXIDE DILATES VESSELS OF THE DISTAL OUTFLOW TRACT

    In separate studies using a porcine anterior segment perfusion model, Susannah Waxman and colleagues, as well as Fiona McDonnell and Dan Stamer, respectively, demonstrate that endogenous nitric oxide can dilate distal vessels of the conventional outflow tract in a TM-independent fashion, establishing distal vessels as an additional site of aqueous outflow resistance.16,17

Glaucoma Horizons

Looking to the future

Uncovering new roles for nitric oxide

New research continues to uncover that nitric oxide lies at a key intersection between IOP-dependent and IOP-independent mechanisms of disease.2,18,19

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References:

1. Steinhorn BS, Loscalzo J, Michel T. Nitroglycerin and nitric oxide—a rondo of themes in cardiovascular therapeutics. N Engl J Med. 2015;373(3):277-280. 2. Reina-Torres E, De Ieso ML, Pasquale LR, et al. The vital role for nitric oxide in intraocular pressure homeostasis. Prog Retin Eye Res. 2021;83:100922. 3. Goldstein IM, Ostwald P, Roth S. Nitric oxide: a review of its role in retinal function and disease. Vision Res. 1996;36(18):2979-2994. 4. Wizemann AJ, Wizemann V. Organic nitrate therapy in glaucoma. Am J Ophthalmol. 1980;90(1):106-109. 5. Nathanson JA. Nitrovasodilators as a new class of ocular hypotensive agents. J Pharmacol Exp Ther. 1992;260(3):956-965. 6. Koshland DE Jr. The molecule of the year. Science. 1992;258(5090):1861. 7. 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(5):2515-2520. 8. 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(9):1765-1773. 9. Tunny TJ, Richardson KA, Clark CV. Association study of the 5' flanking regions of endothelial-nitric oxide synthase and endothelin-1 genes in familial primary open-angle glaucoma. Clin Exp Pharmacol Physiol. 1998;25(1):26-29. 10. 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. Investigative Ophthalmology & Visual Science. 2010;51(2):971-979. 11. 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(6):757-760. 12. Doganay S, Evereklioglu C, Turkoz Y, Er H. Decreased nitric oxide production in primary open-angle glaucoma. Eur J Ophthalmol. 2002;12(1):44-48. 13. 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(13):9438-9444. 14. Ashpole NE, Overby DR, Ethier CR, Stamer WD. Shear stress-triggered nitric oxide release from Schlemm’s canal cells. Invest Ophthalmol Vis Sci. 2014;55(12):8067-8076. 15. Kang JH, Willett WC, Rosner BA, Buys E, Wiggs JL, Pasquale LR. Association of dietary nitrate intake with primary open-angle glaucoma: a prospective analysis from the Nurses’ Health Study and Health Professionals Follow-up Study. JAMA Ophthalmol. 2016;134(3):294-303. 16. Waxman S, Wang C, Dang Y, et al. Structure-function changes of the porcine distal outflow tract in response to nitric oxide. Invest Ophthalmol Vis Sci. 2018;59(12):4886-4895. 17. McDonnell F, Dismuke WM, Overby DR, Stamer WD. Pharmacological regulation of outflow resistance distal to Schlemm's canal. Am J Physiol Cell Physiol. 2018;315(1):C44-C51. 18. Aliancy J, Stamer WD, Wirostko B. A review of nitric oxide for the treatment of glaucomatous disease. Ophthalmol Ther. 2017;6(2):221-232. 19. 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(4):494-498.