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Role of nitric oxide in murine conventional outflow physiology

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Title: Role of nitric oxide in murine conventional outflow physiology
Authors: Chang, JYH
Stamer, WD
Bertrand, J
Read, AT
Marando, CM
Ethier, CR
Overby, DR
Item Type: Journal Article
Abstract: Elevated intraocular pressure (IOP) is the main risk factor for glaucoma. Exogenous nitric oxide (NO) decreases IOP by increasing outflow facility, but whether endogenous NO production contributes to the physiological regulation of outflow facility is unclear. Outflow facility was measured by pressure-controlled perfusion in ex vivo eyes from C57BL/6 wild-type (WT) or transgenic mice expressing human endothelial NO synthase (eNOS) fused to green fluorescent protein (GFP) superimposed on the endogenously expressed murine eNOS (eNOS-GFPtg). In WT mice, exogenous NO delivered by 100 μM S-nitroso-N-acetylpenicillamine (SNAP) increased outflow facility by 62 ± 28% (SD) relative to control eyes perfused with the inactive SNAP analog N-acetyl-d-penicillamine (NAP; n = 5, P = 0.016). In contrast, in eyes from eNOS-GFPtg mice, SNAP had no effect on outflow facility relative to NAP (−9 ± 4%, P = 0.40). In WT mice, the nonselective NOS inhibitor NG-nitro-l-arginine methyl ester (l-NAME, 10 μM) decreased outflow facility by 36 ± 13% (n = 5 each, P = 0.012), but 100 μM l-NAME had no detectable effect on outflow facility (−16 ± 5%, P = 0.22). An eNOS-selective inhibitor (cavtratin, 50 μM) decreased outflow facility by 19 ± 12% in WT (P = 0.011) and 39 ± 25% in eNOS-GFPtg (P = 0.014) mice. In the conventional outflow pathway of eNOS-GFPtg mice, eNOS-GFP expression was localized to endothelial cells lining Schlemm's canal and the downstream vessels, with no apparent expression in the trabecular meshwork. These results suggest that endogenous NO production by eNOS within endothelial cells of Schlemm's canal or downstream vessels contributes to the physiological regulation of aqueous humor outflow facility in mice, representing a viable strategy to more successfully lower IOP in glaucoma.
Issue Date: 3-Jun-2015
Date of Acceptance: 30-May-2015
URI: http://hdl.handle.net/10044/1/49405
DOI: https://dx.doi.org/10.1152/ajpcell.00347.2014
ISSN: 0363-6143
Publisher: American Physiological Society
Start Page: C205
End Page: C214
Journal / Book Title: American Journal of Physiology - Cell Physiology
Volume: 309
Issue: 4
Copyright Statement: © 2015 the American Physiological Society.
Sponsor/Funder: National Institutes of Health
Funder's Grant Number: 203-1774
Keywords: Science & Technology
Life Sciences & Biomedicine
Cell Biology
Physiology
nitric oxide
aqueous humor outflow
glaucoma
intraocular pressure
mouse model
HUMAN TRABECULAR MESHWORK
SOLUBLE GUANYLATE-CYCLASE
ARGININE METHYL-ESTER
SCHLEMMS CANAL CELLS
OPEN-ANGLE GLAUCOMA
INTRAOCULAR-PRESSURE
CILIARY MUSCLE
IN-VIVO
AQUEOUS OUTFLOW
ENDOTHELIAL-CELLS
Animals
Aqueous Humor
Female
Glaucoma
Humans
Intraocular Pressure
Male
Mice
Mice, Inbred C57BL
Mice, Transgenic
Nitric Oxide
Nitric Oxide Synthase Type III
0601 Biochemistry And Cell Biology
0606 Physiology
1116 Medical Physiology
Publication Status: Published
Appears in Collections:Faculty of Engineering
Bioengineering



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