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Nonsulfhydryl-reactive phenoxyacetic acids increase aqueous humor outflow facility
D L Epstein1, B C Roberts, L L Skinner
1Department of Ophthalmology, Duke University Medical Center, Duke University Eye Center, Durham, North Carolina 27710, USA.
Investigative Ophthalmology & Visual Science
|July 1, 1997
Summary
New phenoxyacetic acids increase aqueous humor outflow, suggesting a new class of glaucoma drugs. These compounds alter human trabecular meshwork cells via a mechanism independent of sulfhydryl reactivity or microtubule disruption.
Area of Science:
- Ophthalmology
- Cell Biology
- Pharmacology
Background:
- Ethacrynic acid (ECA) shows potential for glaucoma therapy by increasing aqueous humor outflow.
- ECA affects human trabecular meshwork (HTM) cells, altering shape and attachment, linked to microtubule (MT) and sulfhydryl (SH) reactivity.
Purpose of the Study:
- Evaluate non-SH reactive phenoxyacetic acids (indacrinone, ticrynafen) and a MT-disrupting drug (vinblastine).
- Investigate the mechanism of action for ECA and related compounds on aqueous outflow and HTM cells.
Main Methods:
- Perfused excised bovine and porcine eyes to measure outflow facility.
- Cultured calf pulmonary artery endothelial and HTM cells to assess cytoskeletal effects after drug treatment.
Main Results:
- Indacrinone, ticrynafen, and vinblastine increased outflow facility.
- Outflow effects of indacrinone and ticrynafen were not inhibited by cysteine, unlike ECA.
- Indacrinone and ticrynafen altered HTM cell shape without affecting beta-tubulin staining, while vinblastine disrupted MTs.
Conclusions:
- Phenoxyacetic acids enhance aqueous outflow and modify HTM cell behavior through a non-SH, non-MT mechanism.
- This suggests a broader class of potential glaucoma therapeutics targeting the HTM.
- Understanding the cellular targets has implications for glaucoma treatment and cytoskeletal function in outflow regulation.