Netarsudil Increases Outflow Facility in Human Eyes Through Multiple Mechanisms

Area of Science:

• Ophthalmology
• Pharmacology
• Cell Biology

Background:

• Netarsudil, a Rho kinase/norepinephrine transporter inhibitor, is under investigation for glaucoma treatment.
• Understanding the mechanism of action of netarsudil's active metabolite, netarsudil-M1, is crucial for its therapeutic development.

Purpose of the Study:

• To investigate the effects of netarsudil-M1 on outflow facility (C), outflow hydrodynamics, and the morphology of the conventional outflow pathway in human eyes.
• To elucidate the specific anatomical targets and mechanisms by which netarsudil-M1 influences aqueous humor drainage.

Main Methods:

• Enucleated human eyes (n=5) were perfused with 0.3 μM netarsudil-M1 or vehicle at a constant pressure of 15 mm Hg for 3 hours.
• Fluorescent microspheres were used to trace outflow patterns, and percentage effective filtration length (PEFL) was calculated.
• Morphological changes in the trabecular meshwork (TM), Schlemm's canal inner wall (IW), and episcleral veins (ESVs) were assessed using advanced microscopy techniques.

Main Results:

• Netarsudil-M1 significantly increased outflow facility (C) by 51% compared to baseline and 102% compared to controls (P < 0.01).
• PEFL was significantly increased in both the IW and ESVs, with a higher PEFL observed in ESVs, correlating positively with increased C (R² = 0.58, P = 0.01).
• Netarsudil-M1 treatment led to a significant increase in juxtacanalicular connective tissue (JCT) thickness and episcleral vein cross-sectional area.

Conclusions:

• Netarsudil-M1 acutely enhances aqueous humor outflow facility by expanding the JCT and dilating the ESVs.
• These structural changes facilitate a redistribution of aqueous humor outflow through a larger area of the IW and ESVs, improving overall drainage.
• The findings provide mechanistic insights into netarsudil's efficacy in managing intraocular pressure in glaucoma.