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H-7 Effect On Outflow Facility After Trabecular Obstruction Following Long-term Echothiophate Treatment In Monkeys

¹ Ophthalmology University Wisconsin Hosp Madison WI

Commercial Relationships:  B.A. Hennes, None; J.L. Seeman, None; B.T. Gabelt, None; P.L. Kaufman, University Wisconsin Hosp P.
Grant Identification: Support: NIH Grant EY02698

Abstract

Purpose: To determine whether H-7 can enhance outflow facility (OF) after trabecular meshwork (TM) obstruction by extracellular material which accumulates after long-term topical treatment of monkeys with echothiophate iodide (ECHO).
Methods: Cynomolgus monkeys (n=4) were treated topically once a day for 36 wks with 150µg ECHO to one eye (5 x 2µl drops); vehicle to the opposite eye (C). Every 3 wks, intraocular pressure (IOP) was measured and slit lamp biomicroscopy (SLE) was done. Every 6 wks, accommodative (ACC) response to 20, 200 and 1000µg of topical pilocarpine (PILO) was measured following ganglionic blockade with 15mg/kg i.m. hexamethonium Br (HEX). When ACC became subsensitive to PILO and IOP became elevated, ECHO was discontinued for one wk, the monkeys received HEX i.m and 100µg atropine sulfate topically in both eyes, and OF was measured by 2-level constant pressure perfusion before and after 300µM H-7 anterior chamber exchange.
Results: Pretreatment compared to 36-wk treatment responses (mean±s.e.m.) for ECHO vs control (C) eyes were: IOP (mmHg) changed from 14.8±0.5 to 19.5±0.5 (ECHO, p<0.01) and from 14.5±0.3 to 15.0±0.4 (C); resting refraction (diopters) changed from -2.8±0.6 to -21.8±1.4 (ECHO) and from -2.8±0.5 to -5.0±0.4 (C); ACC response (diopters) to PILO changed from 1.6±2.0 to -0.5±1.3 (ECHO) and 2.8±0.7 to 1.5±0.0 (C) after 20µg, 11.6±2.3 to 0.9±1.2 (ECHO) and 15.3±2.6 to 7.5±1.9 (C) after 200µg, and 19.8±3.2 to 2.7±1.5 (ECHO) and 21.7±3.2 to 16.9±2.3 (C) after 1000µg. SLE revealed no signs of toxicity. Baseline OF (µl/min/mmHg) was 0.17±0.04 ECHO and 0.29±0.06 C. H-7 increased OF compared to baseline by 146% (ECHO, OF=0.45±0.16) vs 258% (C, OF=1.06±0.26).
Conclusion: Long-term ECHO treatment increased IOP, decreased the ACC response to PILO (previously reported) and decreased OF. H-7, which acts in part by disrupting the actin cytoskeleton, increased the reduced OF perhaps by inducing washout of ECM accumulated as a result of long-term ECHO treatment. Periodic measurement of OF in the presence and absence of continued ECHO treatment will determine if the densified meshwork has been permanently re-expanded by a single dose of H-7.

Keywords: 503 outflow: trabecular meshwork • 304 accommodation • 403 extracellular matrix

© 2002, The Association for Research in Vision and Ophthalmology, Inc., all rights reserved. For permission to reproduce any part of this abstract, contact the ARVO Office at arvo{at}arvo.org.