Nonsulfhydryl-reactive phenoxyacetic acids increase aqueous humor outflow facility.
OBJECTIVE
The phenoxyacetic acid, ethacrynic acid (ECA), has potential use in glaucoma therapy because it acts to increase aqueous outflow in vivo and in vitro. In human trabecular meshwork (HTM) cell culture, ECA acts to change cell shape and attachment, effects that have been correlated with microtubule (MT) alterations and chemical sulfhydryl (SH) reactivity. To further explore these actions, we evaluated two non-SH reactive phenoxyacetic acids, inadcrinone and ticrynafen, and the MT-disrupting drug vinblastine.


METHODS
Excised bovine and porcine eyes were perfused and outflow facility measured. Calf pulmonary artery endothelial and HTM cells were grown in culture and cytoskeletal effects evaluated after drug treatment.


RESULTS
Indacrinone, ticrynafen, and vinblastine all caused an increase in outflow facility. In contrast with ECA, the outflow effects of indacrinone and ticrynafen were not blocked by excess cysteine. Although indacrinone and ticrynafen produced changes in cell shape in vitro, the beta-tubulin staining pattern of treated cells was not altered. Vinblastine caused cell shape change and the expected MT disruption.


CONCLUSIONS
Phenoxyacetic acids can increase aqueous outflow facility and alter HTM cell shape and attachment in vitro by a non-SH, non-MT mechanism (which is probably shared also by ECA). These findings suggest the possibility of a broader class of glaucoma drugs that may be directed at the HTM. An understanding of the cellular target for these drugs has implications both for potential glaucoma therapy and for the cytoskeletal mechanisms involved in normal outflow function.
Epstein
D L
DL
Department of Ophthalmology, Duke University Medical Center, Duke University Eye Center, Durham, North Carolina 27710, USA.
Roberts
B C
BC
Skinner
L L
LL
D000818:Animals; D001082:Aqueous Humor / Q000502:physiology*; D002417:Cattle; D002478:Cells, Cultured; D003599:Cytoskeleton / Q000187:drug effects; D004730:Endothelium, Vascular / Q000166:cytology / Q000187:drug effects; D006801:Humans; D066298:In Vitro Techniques; D007189:Indans / Q000494:pharmacology*; D011651:Pulmonary Artery / Q000166:cytology / Q000187:drug effects; D013438:Sulfhydryl Compounds / Q000494:pharmacology; D013552:Swine; D013989:Ticrynafen / Q000494:pharmacology*; D014129:Trabecular Meshwork / Q000166:cytology / Q000187:drug effects; D014747:Vinblastine / Q000494:pharmacology
D007189:Indans; D013438:Sulfhydryl Compounds; D014747:Vinblastine; C013352:indacrinone; D013989:Ticrynafen