NONSULFHYDRYL-REACTIVE PHENOXYACETIC ACIDS INCREASE AQUEOUS-HUMOR OUTFLOW FACILITY

Purpose. 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, E CA acts to change cell shape and attachment effects that have been cor related with microtubule (MT) alterations and chemical sulfhydryl (SH) reactivity. To further explore these actions, we evaluated two non-SH reactive phenoxyacetic acids, indacrinone and ticrynafen, and the MT- disrupting drug vinblastine. Methods. Excised bovine and porcine eyes were perfused and outflow facility measured. Calf pulmonary artery end othelial 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 wi th ECA, the outflow effects of indacrinone and ticrynafen were not bla cked by excess cysteine. Although indacrinone and ticrynafen produced changes in cell shape in vitro, the beta-tubulin staining pattern of t reated cells was not altered. Vinblastine caused cell shape change and the expected MT disruption. Conclusions. Phenoxyacetic acids can incr ease 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 th e cellular target for these drugs has implications both for potential glaucoma therapy and for the cytoskeletal mechanisms involved in norma l outflow function.