Outflow facility in human eyes through multiple mechanisms

Ruiyi Ren, Guorong Li, Thuy Duong Le, Casey Kopczynski, W. Daniel Stamer, Haiyan Gong

Research output: Contribution to journalArticlepeer-review

87 Scopus citations

Abstract

PURPOSE. Netarsudil is a Rho kinase/norepinephrine transporter inhibitor currently in phase 3 clinical development for glaucoma treatment. We investigated the effects of its active metabolite, netarsudil-M1, on outflow facility (C), outflow hydrodynamics, and morphology of the conventional outflow pathway in enucleated human eyes. METHODS. Paired human eyes (n = 5) were perfused with either 0.3 lM netarsudil-M1 or vehicle solution at constant pressure (15 mm Hg). After 3 hours, fluorescent microspheres were added to perfusion media to trace the outflow patterns before perfusion-fixation. The percentage effective filtration length (PEFL) was calculated from the measured lengths of tracer distribution in the trabecular meshwork (TM), episcleral veins (ESVs), and along the inner wall (IW) of Schlemm’s canal after global and confocal imaging. Morphologic changes along the trabecular outflow pathway were investigated by confocal, light, and electron microscopy. RESULTS. Perfusion with netarsudil-M1 significantly increased C when compared to baseline (51%, P < 0.01) and to paired controls (102%, P < 0.01), as well as significantly increased PEFL in both IW (P < 0.05) and ESVs (P < 0.01). In treated eyes, PEFL was significantly higher in ESVs than in the IW (P < 0.01) and was associated with increased cross-sectional area of ESVs (P < 0.01). Percentage effective filtration length in ESVs positively correlated with the percentage change in C (R2 = 0.58, P = 0.01). A significant increase in juxtacanalicular connective tissue (JCT) thickness (P < 0.05) was found in treated eyes compared to controls. CONCLUSIONS. Netarsudil acutely increased C by expansion of the JCT and dilating the ESVs, which led to redistribution of aqueous outflow through a larger area of the IW and ESVs.

Original languageEnglish (US)
Pages (from-to)6197-6209
Number of pages13
JournalInvestigative Ophthalmology and Visual Science
Volume57
Issue number14
DOIs
StatePublished - Nov 1 2016
Externally publishedYes

Keywords

  • Confocal microscopy
  • Effective filtration area
  • Episcleral veins
  • Light microscopy
  • Morphology
  • Netarsudil
  • Ocular perfusion
  • Rho kinase inhibitor
  • Schlemm’s canal
  • Trabecular meshwork
  • Transmission electron microscopy

ASJC Scopus subject areas

  • Ophthalmology
  • Sensory Systems
  • Cellular and Molecular Neuroscience

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