Nitric Oxide (NO): An Emerging Target for the Treatment of Glaucoma

Abstract

The predominant risk factor for the progression of glaucoma is an increase in IOP, mediated via a reduction in aqueous outflow through the conventional (trabecular meshwork and Schlemm's canal) outflow pathway. Current IOP lowering pharmacological strategies target the uveoscleral (nonconventional) outflow pathway or aqueous humor production; however, to date no therapy that primarily targets the conventional pathway exists. Nitric oxide (NO) is an intracellular signaling molecule produced by endogenous NO synthases, well-known for its key role in vasodilation, through its action on smooth muscle cells. Under physiological conditions, NO mediates a multitude of diverse ocular effects, including maintenance of IOP. Nitric oxide donors have been shown to mediate IOP-lowering effects in both preclinical models and clinical studies, primarily through cell volume and contractility changes in the conventional outflow tissues. This review is focused on evaluating the current knowledge of the role and mechanism of action of endogenous NO and NO donors in IOP regulation. Data on key additional functions of NO in glaucoma pathology (i.e., ocular blood flow and effects on optic neuropathy) are also summarized. The potential for future therapeutic application of NO in the treatment of glaucoma is then discussed.

Pharmacotherapy of Glaucoma

“…113 Soluble guanylate cyclases are activated by nitric oxide and generate the secondary signaling molecule cyclic guanosine monophosphate, a pathway that has been extensively studied for its potential to lower IOP. 114 Nitric oxide donors reduce IOP through cell volume and contractility changes in the conventional outflow tissues. In addition, nitric oxide plays a key role in regulating ocular blood flow.…”

The Influence of the Autonomic Nervous System on the Human Choroid

“…Although the exact mechanism underlying these changes is unclear, alterations in the , 1991), existence of nitrergic fibres that label for eNOS in the trabecular meshwork, Schlemm's canal and collecting channels (Cavet et al, 2014), and nNOS in the trabecular meshwork and in the limbus (May et al, 2002;Selbach et al, 2000).…”

“…The cells in the trabecular meshwork and the juxtacanalicular tissue form the second contractile system involving myofibroblasts (Vanhoutte et al, 2009, Cavet et al, 2014 that are particularly numerous in the region next to the scleral spur (Hinz et al, 2007). These contractile myofibroblasts are innervated by cholinergic and nitrergic nerve terminals containing nNOS (Selbach et al, 2000;May et al, 2002).…”

“…During the last two decades it has become clear that nitric oxide plays a key role in the regulation of many physiological processes in the eye, including the regulation of eye growth, ocular blood flow, contraction and permeability of the human conventional outflow pathway cells (Toda and Nakanishi-Toda, 2007;Ellis et al, 2010;Nickla et al, 2013b;Heyne et al, 2013, Cavet et al, 2014. These studies have triggered substantial interest in the identification of ways to therapeutically modulate NO signaling without the need for muscarinic receptor stimulation.…”

“…Over the past five-10 years, several novel approaches to modulate NO signaling have been proposed, including increased time spent outdoors since increased light stimulates synthesis and release of NO from the retina (Hoshi et al, 2003;French et al, 2013Carr and Stell, 2016), nitric oxide-donating latanoprost (Latanoprostene bunod -LBN), which triggers the NO/cGMP signaling cascade promoting rearrangement of cytoskeletal architecture and increased cell relaxation (Cavet et al, 2014;Garcia et al, 2016), or dietary supplements (i.e. inorganic nitrate in the form of beetroot juice) that act as a substrate for NO formation (van Faassen et al, 2009;Weitzberg and Lundberg, 2013).…”