Effects of ethacrynic acid on Schlemm's canal inner wall and outflow facility in human eyes.
OBJECTIVE
The role of the inner wall of Schlemm's canal in determining aqueous outflow facility is poorly understood. To quantify the relationship between inner wall pore characteristics and aqueous outflow facility in human eyes, both control eyes and eyes in which facility had been pharmacologically increased by ethacrynic acid (ECA) infusion were studied.


METHODS
Outflow facility was measured in enucleated human eyes before and after delivery of 0.25 mM ECA (one eye of each of 6 pairs) or 2.5 mM ECA (one eye of each of 13 pairs). ECA, and vehicle in contralateral eyes, was delivered into Schlemm's canal by retroperfusion, thereby largely avoiding drug exposure to the trabecular meshwork. After facility measurement, eyes were fixed under conditions of either constant pressure (physiological intraocular pressure, 13 pairs) or "equal flow" (6 pairs) and were microdissected to expose the inner wall of Schlemm's canal. The density and diameter of intercellular and intracellular inner wall pores were measured using scanning electron microscopy.


RESULTS
Retroperfusion with 2.5 mM ECA increased facility by 73% (P < 0.001), whereas 0.25 mM ECA increased facility by 19% (not statistically significant). The density of intercellular pores in the inner wall of Schlemm's canal was increased by 520% in 2.5 mM ECA-retroperfused eyes (P < 0.00004), whereas intracellular pore density remained approximately constant. Large pores (size > or = 1.1 microm) were particularly enhanced in ECA retroperfused eyes. The net change in facility due to ECA was not correlated with changes in pore density or other inner wall pore statistics.


CONCLUSIONS
Our data are most consistent with a model in which pores in the inner wall of Schlemm's canal indirectly influence facility. However, measured changes in facility due to changes in inner wall properties did not agree with quantitative predictions of the pore funneling theory, suggesting that changes in facility may instead be due to gel leakage from the extracellular spaces of the juxtacanalicular tissue. More definitive experiments are required to confirm this hypothesis.
Ethier
C R
CR
Department of Mechanical and Industrial Engineering, University of Toronto, Ontario, Canada.
Coloma
F M
FM
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000867:Anterior Chamber / Q000187:drug effects* / Q000378:metabolism / Q000648:ultrastructure; D001082:Aqueous Humor / Q000378:metabolism*; D002473:Cell Wall / Q000187:drug effects; D004232:Diuretics / Q000494:pharmacology*; D004976:Ethacrynic Acid / Q000494:pharmacology*; D005260:Female; D006801:Humans; D008297:Male; D008855:Microscopy, Electron, Scanning; D010477:Perfusion; D016062:Porosity / Q000187:drug effects; D011312:Pressure; D012590:Sclera / Q000187:drug effects* / Q000378:metabolism / Q000648:ultrastructure
D004232:Diuretics; D004976:Ethacrynic Acid