Effect of Nitric Oxide on Anterior Segment Physiology in Monkeys

Heyne, Galen W.; Kiland, Julie A.; Kaufman, Paul L.; Gabelt, B’Ann T.

doi:10.1167/iovs.12-11491

Cited by 60 publications

(65 citation statements)

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“…In human eyes, NOS reactivity was enriched in major sites of outflow resistance, including the TM and SC, as well as in collecting channels. 16 The NO-donating compounds effectively decrease conventional outflow resistance, leading to a decrease in IOP and outflow rate in different animal models, including rabbits, 21-24 pigs, 25 dogs, 22 and monkeys, 22,26 and in perfused postmortem human eyes. 27,28 Our previous study 29 further showed that eNOS/NO is a key regulator of outflow facility and…”

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confidence: 99%

Endothelial Nitric Oxide Synthase-Related Mechanotransduction Changes in Aged Porcine Angular Aqueous Plexus Cells

Lei

Stamer

et al. 2014

Investigative Ophthalmology & Visual Science

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Citation: Lei Y, Stamer WD, Wu J, Sun X. Endothelial nitric oxide synthaserelated mechanotransduction changes in aged porcine angular aqueous plexus cells. Invest Ophthalmol Vis Sci. 2014;55:8402-8408. DOI: 10.1167/iovs.14-14992 PURPOSE. To investigate effects of aging on endothelial nitric oxide synthase (eNOS) expression and signaling in angular aqueous plexus (AAP) (functional equivalent to human Schlemm's canal) cells subjected to shear stress. METHODS.The AAP cells were isolated differentially from porcine outflow tissues using puromycin selection. Cell aging was induced by culturing cells in hyperoxia condition (40% oxygen and 5% carbon dioxide) for 14 days. The AAP cells grown in chamber slides were exposed to a shear stress of 8 dynes/cm 2 for 24 hours. Expression of eNOS, eNOS-phospho Thr495, eNOS-phospho Ser1177, and Akt-phospho was tested by Western blot analysis and immunofluorescence staining. Nitric oxide (NO) levels were measured using the Griess assay. RESULTS.Compared with control, eNOS levels in aged cells were significantly reduced by 60% (P < 0.05; n ¼ 6). Phosphorylation of eNOS at Ser1177 and Akt at Ser473 was 63% and 80% lower in aged cells, respectively, whereas phosphorylation of the eNOS inhibition site (Thr495) increased by 6.1-fold (P < 0.05; n ¼ 6). Shear stress (8 dynes/cm 2 for 24 hours) increased eNOS abundance (total protein and at cell borders) and phosphorylation at Ser1177 by 1.7-fold and 1.8-fold, respectively (P < 0.05; n ¼ 6), whereas aged cells were unresponsive. In control cells exposed to shear stress, the NO concentration was 1.8-fold higher than in the static group (P < 0.05; n ¼ 4); however, aged cells were unresponsive to shear stress (mean 6 SD, 4.3 6 1.3 vs. 4.1 6 1.4 lM).CONCLUSIONS. Aged AAP cells appear compromised in their mechanotransduction machinery involving eNOS, the protein product of the gene, NOS3, polymorphisms of which impart a risk for the development of glaucoma.Keywords: aging, Schlemm's canal, eNOS G laucoma comprises a group of complex and heterogeneous blinding diseases, affecting almost 60 million people worldwide. 1 Clinically, glaucoma is characterized by cupping of the optic nerve head and visual field loss. Elevated IOP is the primary risk factor for glaucomatous optic nerve damage, and reducing pressure remains the only treatable end point that slows or stops disease progression. The risk of developing POAG also clearly increases with age. 2-8 Primarily, IOP is determined by changes in aqueous humor outflow resistance, which is thought to reside mainly in the juxtacanalicular region, where the trabecular meshwork (TM) and the inner wall of Schlemm's canal (SC) cells interact. 9,10 The endothelial cells of the inner wall of SC are important in regulating outflow resistance and thus IOP. 11,12Nitric oxide (NO) regulation appears to have a role in POAG. Family association studies [13][14][15] show a relationship between NOS3 gene polymorphisms, which encode for endothelial NO synthase (eNOS), and POAG. These recent findings are consistent wit...

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confidence: 99%

Endothelial Nitric Oxide Synthase-Related Mechanotransduction Changes in Aged Porcine Angular Aqueous Plexus Cells

Lei

Stamer

et al. 2014

Investigative Ophthalmology & Visual Science

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“…Independent lines of investigation consistently reported on the ability of NO to relax TM and Schlemm's canal (SC) that ultimately results in enhanced trabecular outflow facility. 7,9,15 Furthermore, NO seems to also affect AH formation at the ciliary epithelium. 6 Both these effects are mediated via soluble guanylyl cyclase activation and cGMP formation.…”

Section: Discussionmentioning

confidence: 99%

Intraocular Pressure–Lowering Activity of NCX 470, a Novel Nitric Oxide–Donating Bimatoprost in Preclinical Models

Impagnatiello

Toris

Batugo

et al. 2015

Invest. Ophthalmol. Vis. Sci.

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PURPOSE. The prostaglandin F2alpha (PGF2a) analogue bimatoprost lowers intraocular pressure (IOP) by increasing uveoscleral outflow at doses shown to elicit redness of the eye. With the aim to enhance the IOP-lowering effect of bimatoprost we studied NCX 470, a dual-acting compound combining bimatoprost with nitric oxide (NO) known to mainly act via relaxation of trabecular meshwork and Schlemm's canal.METHODS. New Zealand white rabbits with transient hypertonic saline-induced IOP elevation (tOHT-rabbits), cynomolgus monkeys with laser-induced ocular hypertension (OHT-monkeys), and normotensive dogs (ONT-dogs) were used. The levels of NCX 470, bimatoprost, and bimatoprost acid were determined in aqueous humor (AH), cornea (CR), and iris/ciliary body (ICB) by liquid chromatography-mass spectrometry/mass (LC-MS/MS), while cGMP in AH and ICB was monitored using an enzyme immunoassay (EIA) kit in pigmented Dutch Belted rabbits.RESULTS. NCX 470 (0.14%, 30 lL) lowered IOP in tOHT-rabbits with an E max of À7.2 6 2.8 mm Hg at 90 minutes. Bimatoprost at equimolar dose (0.1%, 30 lL) was noneffective in this model. NCX 470 (0.042%, 30 lL) was more effective than equimolar (0.03%, 30 lL) bimatoprost in ONT-dogs (IOP change, À5.4 6 0.7 and À3.4 6 0.7 mm Hg, respectively, P < 0.05) and in OHT-monkeys (IOP change, À7.7 6 1.4 and À4.8 6 1.7 mm Hg, respectively, P < 0.05) at 18 hours post dosing. NCX 470 (0.042%, 30 lL) or bimatoprost (0.03%, 30 lL) resulted in similar bimatoprost acid exposure in AH, CR, and ICB while cGMP was significantly increased in AH and ICB at 18 and 24 hours after NCX 470 dosing.CONCLUSIONS. NCX 470 lowers IOP more than equimolar bimatoprost in three animal models of glaucoma by activating PGF2a and NO/cGMP signaling pathways.

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“…Additionally, several studies have reported that blockage of pre-junctional M2/M4 muscarinic receptors on cholinergic-nitrergic nerve terminals by atropine causes release of neural nitric oxide from the nerve terminals, followed by a vasodilation response in ocular blood vessels (Ayajiki et al, 2000;Toda and Nakanishi -Toda, 2007), as well as decreased contraction of trabecular meshwork cells forming conventional outflow cells (Ellis et al, 2010;Heyne et al, 2013). Further, Schlemm's canal endothelial cells are enriched with the NO-producing enzyme eNOS (Nathanson and McKee, 1995).…”

Section: Discussionmentioning

confidence: 99%

“…Additionally, immunohistochemical studies have shown an increased NOS activity in the longitudinal compared with the circular regions of the ciliary muscle in healthy human eyes (Nathanson andMcKee, 1995, Chen et al, 1998) and a dramatic decrease in NOS activity in human glaucoma eyes compared with control eyes (Nathanson and McKee, 1995, Chen et al, 1998, Heyne et al, 2013. Thus, it is possible that the lack of subsequent elevation of IOP after homatropine instillation in our study is related to a relaxation of longitudinal portion of the ciliary muscle that causes a decrease in tension transmitted directly to the trabecular meshwork and Schlemm's canal.…”

Section: Discussionmentioning

confidence: 99%

“…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.…”

Section: Limitations and Further Study Recommendationsmentioning

confidence: 99%

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The Influence of the Autonomic Nervous System on the Human Choroid

Sander¹

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v AbstractThe impact of myopia is greater than just its optical consequences and in severe cases it can lead to a loss of vision. It is a highly prevalent eye disorder, with about one third of the population worldwide affected by this refractive error. Despite extensive research, the pathogenesis of myopia is still only partially understood. An improved knowledge of mechanisms underlying myopia is critical to developing new therapies to prevent myopia or to slow its progression.Although there is no fully effective and satisfactory myopia control treatment available, growing evidence has suggested that the choroid has a passive or active role in the regulation of eye growth and refractive error development. Numerous human and animal studies have shown that the retina can be moved forward or backward towards the image plane through changes in choroidal thickness, and these changes are likely to be associated in the longer term with eye growth and the development of refractive errors. As the choroid receives a rich innervation from the autonomic nervous system, many previous animal studies have utilized pharmacological agents and neurotoxins to elucidate the possible role of muscarinic signaling in the regulation of choroidal thickness, but only a few studies have investigated this issue in humans. An improved understanding of the mechanisms that control choroidal thickness may be important in developing new therapies for combating the development and progression of myopia.The research described in the thesis aimed to investigate the role of the autonomic nervous system in the control of choroidal thickness, axial length and the morphology In a series of experiments, we have confirmed that in humans under normal visual conditions, the parasympathetic nervous system is involved in the short-term regulation of subfoveal and parafoveal choroidal thickness, axial length and the morphology of the anterior sclera. The muscarinic blocker homatropine caused a significant subfoveal and parafoveal choroidal thickening, shortening of axial length, an enlargement of Schlemm's canal area and an increase in thickness of the conjunctival/episcleral complex. On the other hand, no notable changes in ocular parameters, except a decrease in the thickness of the conjunctival/episcleral tissues were found after instillation of the sympathomimetic drug phenylephrine.In an attempt to further improve our understanding of the myopigenic mechanisms influencing the thickness of the choroid in humans, we investigated the short-term influence of mixed interventions (positive and negative lens-imposed defocus / 2% homatropine) on choroidal thickness and axial length in emmetropic and myopic subjects. Homatropine prevented choroidal thinning in response to hyperopic defocus.This finding is consistent with the anti-myopia effects of muscarinic blockers and supports the potential importance of hyperopic defocus in the development of human myopia. By contrast, co-administration of homatropine with myopic defocus did not enhance the thicken...

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Effect of Nitric Oxide on Anterior Segment Physiology in Monkeys

Cited by 60 publications

References 35 publications

Endothelial Nitric Oxide Synthase-Related Mechanotransduction Changes in Aged Porcine Angular Aqueous Plexus Cells

Endothelial Nitric Oxide Synthase-Related Mechanotransduction Changes in Aged Porcine Angular Aqueous Plexus Cells

Intraocular Pressure–Lowering Activity of NCX 470, a Novel Nitric Oxide–Donating Bimatoprost in Preclinical Models

The Influence of the Autonomic Nervous System on the Human Choroid

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